Pyrazole-based thyroid receptor compounds

ABSTRACT

The present invention discloses a novel thyroid like compounds of formula (I), wherein R 1  R2, R 3 , R 4  and Z are as defined in the specification, method for its preparation, composition containing such compounds and use of such compounds and composition as medicament. Further, compounds of formula (I) has significantly low binding affinity to thyroid receptors and thus considerably devoid of thyrotoxic effects. The invention also relates to the use of the compound of formula (I) for the preparation of a medicament for treating various disease conditions such as obesity, dyslipidemia, metabolic syndrome and co-morbidities associated with metabolic syndrome.

This is a Divisional application of application Ser. No. 12/224,168,filed Aug. 20, 2008, which is a nationalization application ofPCT/IN08/000345 filed Jun. 2, 2008, published in English, which claimsbenefit of Indian Application 857/KOL/2007 filed Jun. 6, 2007.

FIELD OF THE INVENTION

The present invention relates to the novel thyroid like compounds offormula (I), wherein R¹, R², R³, R⁴ and Z are as defined hereinafter,method for its preparation, composition containing such compounds anduse of such compounds and composition in therapy. Further, compounds offormula (I) has significantly low binding affinity to thyroid receptorsand thus considerably devoid of thyrotoxic effects. The invention alsorelates to the use of the compound of formula (I) for the preparation ofa medicament for treating various disease conditions such as obesity,dyslipidemia, metabolic syndrome and co-morbidities associated withmetabolic syndrome.

BACKGROUND OF THE INVENTION AND PRIOR ART

Obesity is a condition of an excessive accumulation of energy in thebody, in which the natural energy reserve, stored in the fatty tissue ofhumans and other mammals, is increased to a point where it is associatedwith certain health conditions or increased mortality. Obesity developsfrom an imbalance between energy expenditure and energy intake, and thephysiological approach to obesity treatment is to achieve a negativeenergy and fat balance. Indeed the weight loss through diet is effectivefor the majority of patient yet very few manage to maintain theirinitial weight loss over the long time.

Obesity has reached epidemic proportions globally, with more than 1.6billion adults overweight—at least 400 million of them clinicallyobese—and is a major contributor to the global burden of chronic diseaseand disability (WHO fact sheet, 2006). WHO further projects that by2015, approximately 2.3 billion adults will be overweight and more than700 million will be obese. At least 20 million children under the age of5 years are overweight globally in 2005. Obesity and overweight pose amajor risk for serious chronic diseases, including type-II diabetes,cardiovascular disease, hypertension, dyslipidemia, metabolic syndrome,stroke, and certain forms of cancer. The health consequences range fromincreased risk of premature death, to serious chronic conditions thatreduce the overall quality of life.

Although obesity has long been associated with serious health issues, ithas only recently been regarded as a disease in the sense of being aspecific target for medical therapy. Consequently, developing obesitytreatments that target novel pathways is a growing focus for bothbiopharmaceutical and the medical device industries (Melnikova I. &Wages D Nature Reviews Drug Discovery (2006); 5: 369-370).

The available therapies for treatment of obesity have proved to be oflimited value either due to inadequate efficacy or due to higher rate ofadverse effects and hence there exists a need for better approach withdesired efficacy having low side effects.

Many of the compounds using various new therapeutic approaches such asNPY receptor antagonist, beta3 agonist etc. are in early stage ofdevelopment. Recently selective thyroid receptor ligands are also beingexplored for the treatment of obesity.

Epidemological evidences clearly reveal the relationship between thealtered carbohydrate and lipid metabolism, accumulation of body fat andcholesterol and subsequent risk of cardiovascular diseases such asatherosclerosis, hypertension etc. Atherosclerosis, a disease of thearteries, is considered to be a leading cause of death worldwide.Epidemiological evidence has clearly established hyperlipidemia as aprimary risk factor leading to cardiovascular disease due toatherosclerosis. In recent years, medical fraternity have placed renewedemphasis on lowering plasma cholesterol levels, and more particularlylow density lipoprotein cholesterol as an essential step for preventionof cardiovascular diseases. The upper limits of “normal” are now knownto be significantly lower than heretofore appreciated. As a result,large segments of populations are now realized to be at particularlyhigh risk. Such independent risk factors include glucose intolerance,left ventricular hypertrophy, hypertension, and being of the male sex.Cardiovascular disease is more prevalent among diabetic subjects, atleast in part due to the existence of multiple independent risk factorsin this population. Successful treatment of dyslipidemia in the generalpopulation, and diabetic subjects in particular, is therefore of utmostclinical importance.

Hypertension is a condition that occurs in the human population as asecondary symptom to various other disorders. However, hypertension isalso evidenced in many patients in whom the causative factors areunknown. While such “essential” hypertension is often associated withdisorders such as obesity, diabetes and hypertriglyceridemia, therelationship between these disorders has not been well established. Manypatients also display the symptoms of high blood pressure in thecomplete absence of any other signs of disease or disorder. It is knownthat hypertension can directly lead to various complications such asheart failure, renal failure and stroke (brain hemorrhaging).Hypertension can also contribute to the development of atherosclerosisand coronary disease. Hypertension rarely manifests alone but usuallyclusters with other cardiovascular risk factors, such as insulinresistance, visceral obesity, and dyslipidemia. These conditionsgradually weaken a patient and can lead to death. Though effective bloodpressure control is generally regarded as the most importantintervention to reduce long-term complications of hypertension thetreatment guidelines are now beginning to incorporate the concept ofglobal cardiovascular risk management to improve patient outcomes.

Metabolic syndrome, a cluster of metabolic abnormalities is acombination of insulin resistance, dyslipidemia, obesity andhypertension, which leads to increased morbidity and mortality bycardiovascular diseases (CVD). In the general population, metabolicsyndrome increases the risk for CVD by a factor of 1.65. The presence ofmetabolic syndrome predicted an increased risk for total andcardiovascular mortality (Eberhard Ritz, Am. J Cardiol (2007); 100[Suppl]: 53-60). In one of the study it is estimated that metabolicsyndrome is present in more than 20% of US adult population. (Young-WooPark et al. Arch intern Med (2003); 163: 427-436)

In type-II diabetes, obesity and dyslipidemia are also highly prevalentand around 70% of people with type 2 diabetes additionally havehypertension once again leading to increased mortality of cardiovasculardiseases.

Metabolic disorders that affect glucose and lipid metabolism such ashyperlipidemia, obesity, diabetes, insulin resistance, hyperglycemia,glucose intolerance, and hypertension have long term health consequencesleading to chronic conditions including cardiovascular disease andpremature morbidity. Such metabolic and cardiovascular disorders may beinterrelated, aggravating or triggering each other and generatingfeedback mechanisms, which is still unclear.

Hence, multifactorial intervention is crucial in the prevention oftype-II diabetes and the reduction of global cardiovascular riskassociated with metabolic syndrome. (Richard Ceska, Diabetes andVascular Disease Research (2007); 4 (suppl): S2-S4) Moreover,multifactorial intervention has proved more beneficial than reducingindividual risk factor for global cardiovascular risk reduction.Currently, there is no single treatment available which simultaneouslyaddresses multiple components of metabolic syndrome.

Thyroid gland in response to stimulation by TSH, produces T4, T3 andrT3. Although T4, T3 and rT3 are generated within the thyroid gland, T4is quantitatively the major secondary product. Production of T3 & rT3within the thyroid is regulated to very small quantities and is notconsidered significant compared to peripheral production. T4 is eitherconverted to T3 or rT3, or eliminated by conjugation, deamination ordecarboxylation. It is estimated that more than 70% of T4 produced inthyroid is eventually deiodinated in peripheral tissues to form T3 orrT3. Although some T3 is produced in the thyroid, approximately 80-85%is generated outside the thyroid, primarily by conversion from T4 inliver and kidney. Further degradation of T3 & rT3 results in theformation of several distinct diiodothyronines: 3,5-T2, 3,3′-T2 and3,5′-T2 (Kelly G S. Altern Med Rev (2000); 5(4): 306-333). Structurallyall thyroid hormones can be divided into two ring i.e. prime ring andnon-prime ring and its SAR suggests unpredictable behaviour of theeffect of substituents at (3′-, 5′-, 3- and 5-) on the prime andnon-prime ring respectively (Burger' 6^(th) edition, vol 3, pp.564-565). T3 is considered to be the most metabolically active thyroidhormone. Various experimental evidences suggest that major effects ofthyroid hormone are mediated by T3. Thyroid hormones affect themetabolism of virtually every cell of the body. At normal levels, thesehormones maintain body weight, the metabolic rate, body temperature, andmood, and influence serum low density lipoprotein (LDL) levels. Thus, inhypothyroidism there is weight gain, high levels of LDL cholesterol, anddepression. In excess with hyperthyroidism, these hormones lead toweight loss, hypermetabolism, lowering of serum LDL levels, cardiacarrhythmias, heart failure, muscle weakness, bone loss in postmenopausalwomen, and anxiety (WO200703419). The brain is also an important targetof thyroid hormone, mainly during development but also in adult animals.Severe neonatal hypothyroidism is associated with alterations incerebellum, especially on granular and Purkinje cells, which exhibitimpaired differentiation and migration; Purkinje cells are hypoplastic,and the granular cells fail to migrate from the external germinal layerto the internal granular layer adequately.

Interestingly, it is known that the thyroid hormone known as thyroxine(“T4”) converts to thyronine (“T3”) in human skin by deiodinase I, aselenoprotein. Selenium deficiency causes a decrease in T3 levels due toa decrease in deiodinase I activity; this reduction in T3 levels isstrongly associated with hair loss. Consistent with this observation,hair growth is a reported side effect of administration of T4.Furthermore, T3 and T4 has been the subject of several patentpublications relating to treatment of hair loss, including, for example,International Patent Application Publication No. WO 00/72810, andWO00/72811,

The use of thyroid hormones is currently limited as a replacementtherapy for patients with hypothyroidism. However, replacement therapy,particularly in older individuals is limited by certain adverse effectsof thyroid hormones. Some effects of thyroid hormones may betherapeutically useful in non-thyroid disorders, if adverse effects canbe minimized or eliminated. These potentially useful features includeweight reduction for the treatment of obesity, cholesterol lowering totreat hyperlipidemia, amelioration of depression and stimulation of boneformation in osteoporosis (Liu Ye et al., JMC (2003); 46: 1580-88) Ithas been found that hyperthyroidism is associated with low total serumcholesterol, which is attributed to thyroid hormone increasing hepaticLDL receptor expression and stimulating the metabolism of cholesterol tobile acids (Abrams J J et. al. J. Lipid Res. (1981); 22: 323-38).Hypothyroidism, in turn, has been associated with hypercholesterolemiaand thyroid hormone replacement therapy is known to lower totalcholesterol (Aviram M. et. al. CUn. Biochem. (1982); 15: 62-66; Abrams JJ et. al. J. Lipid Res. (1981); 22: 323-38). Thyroid hormone has beenshown in animal models to have the beneficial effect of increasing HDLcholesterol and improving the ratio of LDL to HDL by increasing theexpression of apo A-I, one of the major apolipoproteins of HDL (Ness GC. et. al. Biochemical Pharmacology, (1998); 56: 121-129; Grover G J.et. al. Endocrinology, (2004); 145: 1656-1661; Grover G J. et. al. Proc.Natl. Acad. Sci. USA, (2003); 100:10067-10072). Through its effects onLDL and HDL cholesterol, it is possible that thyroid hormones may alsolower the risk of atherosclerosis and other cardiovascular diseases.Additionally, there is evidence that thyroid hormones lower Lipoprotein(a), an important risk factor which is elevated in patients withatherosclerosis (Paul Webb. Expert Opin. Investig. Drugs, (2004); 13(5):489-500; de Bruin et. al. J. CUn. Endo. Metab., (1993); 76: 121-126).

Prior attempts to utilize thyroid hormones pharmacologically to treatthese disorders have been limited by manifestations of hyperthyroidismand in particular by cardiovascular toxicity (Thyrotoxicosis) (Liu Ye etal., JMC (2003); 46: 1580-88).

Thyroid hormone exerts there effects through thyroid receptors. Thereare two major subtypes of thyroid receptors located within the nucleus(Genomic effect) TRα and TRβ. TRα1, TRβ1 and TRβ2 isoforms bind thyroidhormone and acts as a ligand regulated transcription factors. The TRα2isoform is prevalent in pituitary and other parts of the CNS, does notbind thyroid hormones and acts in many context as a transcriptionalrepressor. TRα1 is also widely distributed. The literature suggests manyor most effects of thyroid hormones on the heart, and in particularheart rate and rhythm are mediated through the TRα1 isoform. On theother hand, most actions of the hormones on the liver and other tissuesare mediated more through the β forms of receptors (Liu Ye et al., JMC(2003); 46: 1580-88).

Thyroid hormone has been demonstrated to modulate the behavior of manymetabolic pathways potentially relevant for the basal metabolic rate. Ingeneral terms, the major candidate mechanisms include uncoupling ofcellular metabolism from adenosine triphosphate (ATP) synthesis, orchanges in the efficiency of metabolic processes downstream from themitochondria. Therefore efforts have been made to synthesize thyroidhormone beta selective and/or tissue selective compounds for thetreatment of metabolic disorders, which are devoid of thyrotoxic sideeffects mediated by TRα receptors.

Thus in effort to make specific TRβ selective Thyroid ligands manyresearchers have tried to synthesize Thyroid mimetics wherein the effectof various prime and non-prime rings and the substituents on it arestudied as disclosed in US20050085541, US20040039028, WO2007003419,WO2006128056, WO200709913, US20010051645, US20020049226 andUS20030040535 all of which are incorporated herein as reference.

Until recently, T3 was found to be more biologically active than T4 andis presently thought to be the predominant activator of the thyroidhormone receptors (Burger' 6^(th) edition, vol 3, pp. 564-565). In thelast decade or so, evidence has accumulated that naturally occurringiodothyronines other than T3 exerts biological effects. Among these,3,5-diiodothyronine appears to be responsible for rapid, short-termeffects on cellular oxidative capacity and respiration rate by directinteraction with mitochondrial binding sites. The accumulated evidencepermits the conclusion that the action of T2 do not simply mimic thoseof T3 but instead are specific action exerted through mechanism that areindependent of those actuated by T3 through thyroid hormone receptors(A. Lombardi. Immun Endoc and Metab Agents in Med Chem (2006); 6:255-65; WO200509433).

Growing body of evidences now suggest that, 3,5-diiodothyronine caninduce metabolic inefficiency, possibly by stimulating energy loss viamechanism involving the mitochondrial apparatus rather that nuclearreceptors. Such an action of T2 can potentially result in a reducedadiposity and less body weight gain without inducing a clinical syndromerelated to thyrotoxic state, by increasing fatty acid influx in tomitochondria and fatty acid oxidation (A. Lombardi. Immun Endoc andMetab Agents in Med Chem (2006); 6: 255-65; Horst C., Biochem J. (1989);261: 945-950). From a clinical point of view a scenario involving highlevel of fatty acid oxidation, reduced fat storage, reduction in serumtriglyceride and cholesterol levels, reduced lever steatosis, reducedbody weight gain without a reduction in calorie/fat intake is anattractive prospect for an intractable obesity (A. Lombardi. Immun Endocand Metab Agents in Med Chem (2006); 6: 255-65).

WO2005/009433 discloses the composition of 3,5 T2 in therapeuticallyeffective doses mainly for use in obesity, hepatic steatosis anddyslipidemia.

In summary, Thyroid hormones and other idothyronine together orindividually influence the metabolism of virtually every cell of thebody. These hormones has important physiological role such as tomaintain body weight, the metabolic rate, body temperature, and mood,and influence serum low density lipoprotein (LDL) levels etc. Thus,thyroid hormones (T4, T3) can cause weight reduction via increasedmetabolic rate and a LDL cholesterol reduction through both anupregulation of LDL receptors and increased cholesterol metabolism.However thyroid hormone do not have sufficiently broad therapeuticwindow, particularly with regard to cardiac acceleration, to be usefulfor treatment of disorders such as obesity and lipid disorders. Veryrecently it has been reported that TRIS selective agonists might beexploited as a therapeutically effective means to lower weight andplasma cholesterol without eliciting deleterious cardiac effects.However, recently it has also been found that the TRβ selective agonistinduce proliferative response like lead to hepatocyte proliferation andalso induced pancreatic acinar cell proliferation (Amedeo columbano.Endocrinology (2006); 147(7): 3211-8). There are also reports that T3increases food consumption at low dosage in animal, independent to itsnuclear effects (Wing May Kong et al. Endocrinology (2004); 145:5252-5258) and the increase in energy intake were also displayed by T2,(Horst et al., J Endocrinology (1995); 145: 291-297) which can becompensatory in the treatment of obesity.

Thus, there exists a need for novel thyroid like compounds, which areuseful for the treatment of metabolic disorders such as obesity, insulinresistance, diabetes, dyslipidemia, fatty liver, metabolic syndrome, anddisorders of altered thyroid function without having undesirable effectssuch as thyrotoxicosis and increase in food consumption.

Accordingly, inventors of the present invention have found novel thyroidlike compounds which are expected to demonstrate a utility for thetreatment or prevention of diseases or disorders associated withinappropriate thyroid hormone activity, for example: 1) The conditionassociated with a disease or disorder associated with excessive fataccumulation, altered mitochondrial function 2) obesity 3) lipiddisorders caused by an imbalance of blood or tissue lipid levels such asdyslipidemia, atherosclerosis 4) impaired glucose tolerance 5) type IIdiabetes 6) replacement therapy 7) depression 8) cardiovascular diseasesand 9) skin disorders and significantly devoid of undesirable effectslike thyrotoxicosis and increase in food consumption.

WO2007027842 relates to an anilinopyrazole compounds useful for thetreatment of diabetes and related disorders. US2004110816 disclosescertain reverse transcriptase inhibitors of pyrazole derivatives usefulfor the treatment of HIV and WO9716422 discloses certain chromanyl andthiochromanyl compounds having retinoid like activity.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWING

FIG. 1 gives a graphical representation of effect of test compound B inOGTT (Oral glucose tolerance test)

SUMMARY OF THE INVENTION

One embodiment of the present invention is a compound of formula (I)

Wherein, R¹ and R³ is same or different, and is independently selectedfrom H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, halo, CN, CF₃, —O—(C₁-C₆)alkyl,—CO₂—(C₁-C₆)alkyl, COOH, —CONH—(C₁-C₆)alkyl, —CONH-aryl, —NH2, —CONH—R⁶,—CONR⁵, —C₁-C₃alkyl-aryl, —(C₁-C₃)alkyl-R⁶, —NH—(C₁-C₆)alkyl, —NHaryl,—NH—SO₂—(C₁-C₆)alkyl, —CH₂—NH—(C₁-C₆)alkyl, —CH₂—O—(C₁-C₆)alkyl,—C₁-C₃alkyl-NR⁵, R⁶, R⁷, wherein C₁-C₆alkyl and C₃-C₇ cycloalkyl isoptionally substituted with one or more substituents selected from(C₁-C₆)alkyl, halo, cyano, —OH, oxo, —COOH, —O—(C₁-C₆)alkyl, —O-benzyl,—COO—(C₁-C₆)alkyl, —CONH—(C₁-C₆)alkyl, —CONR⁵, —CONH-aryl,—CONH-heteroaryl or —CH₂NR⁵;

R² is selected from (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)alkenyl,(C₃-C₆)alkynyl, —C(O)—(C₁-C₃)alkyl-COOH, —(C₁-C₃)alkyl-COOH,—C(O)—(C₁-C₃)alkyl-COO-alkyl, —C(O)—C(O)O—(C₁-C₆)alkyl,—C(O)—(C₁-C₃)alkyl-NH—(C₁-C₆)alkyl, —C(O)—O—(C₁-C₆)alkyl, —C(O)NR⁵,—C(O)NH—(C₁-C₆)alkyl, —C(O)—(C₁-C₃)alkylaryl, —C(O)—(C₁-C₃)alkyl-R⁶, R⁶,R⁷, wherein said (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)alkenyl,(C₃-C₆)alkynyl being optionally substituted with one or moresubstituents selected from perhaloalkyl, Oxo, —C(O)OH,—C(O)—O—(C₁-C₃)alkyl, —C(O)—O—(C₁-C₃)alky-laryl,—C(O)—O—(C₁-C₃)alkyl-R⁶, —CONH₂, —CONH(C₁-C₃)alkyl, —C(O)NH-aryl,—C(O)NH—R⁶, —CONR⁵—CONHNH₂, —C(═NH)NH—(C₁-C₆)alkyl, —C(═NH)NH₂,C(═NH)NHOH, —C(O)—R⁸, —C(O)NHSO₂(C₁-C₆)alkyl, —C(O)NHSO₂-aryl,—C(O)NHOH, —C(O)NHSO₂—R⁶, —C(O)NHNH—(C₁-C₆)alkyl, —C(O)NHNH-aryl,—CONH—(C₁-C₂)alkyl-aryl, —C(O)NH—(C₁-C₂)alkyl-R⁶, —CH₂NR⁵, —NH₂,—NH—(C₁-C₆)alkyl, —NH—C(O)—O—(C₁-C₃)alkyl, —NH—C(O)—(C₁-C₃)alkyl,—NHC(O)-aryl, —NHC(O)—(C₁-C₃)alkylaryl, —NHC(O)—R⁶, —NH—C(O)NR⁵,—NH—C(O)NH-aryl, —NHC(O)NH—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl,—NH—SO₂-aryl, —NH—SO₂—R⁶, halo, cyano, —OH, —O—(C₁-C₆)alkyl, —O-aryl,—O-heteroaryl, —O—(C₁-C₂)alkyl-aryl, —SO₃H, —SO₂NH-aryl, —SO₂NH—R⁶ or—SO₂NH—(C₁-C₆)alkyl, R⁶ or R⁷;

R⁵ together with Nitrogen atom to which it is attached form a saturatedor unsaturated (C₃-C₆) membered ring, which may further contain 1-2heteroatoms selected from O, N or S and which may be optionallysubstituted with one or more substituents selected from oxo, —COOH,halo, —OH, —O—(C₁-C₆)alkyl, or —(C₁-C₆)alkyl;

R⁶ is selected from phenyl or 5-8 membered heteroaryl containing 1-4heteroatoms selected from O, N or S, wherein said heteroaryl or phenylring being optionally substituted with one or more substituents selectedfrom halogen, —OH, -perhaloalkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,—SO₂(C₁-C₆)alkyl, cyano, —COOH, —C(O)O—(C₁-C₆)alkyl, —C(O)O—CH₂-aryl,—C(O)O-aryl, —CONH(C₁-C₃)alkyl, nitro, —NH₂, —NH—(C₁-C₆)alkyl,—NHC(O)—(C₁-C₆)alkyl, —NHC(O)-aryl, —NHSO₂(C₁-C₆)alkyl, —CONH₂,—SO₂—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl or —COR⁸;

R⁷ is a 3-6 membered heterocyclic ring containing 1-4 heteroatomselected from O, N or S, and the said heterocyclic ring being optionallysubstituted with one or more substituents selected from oxo, halogen,—O—(C₁-C₆)alkyl, —OH, —CF₃, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano,—COOH, —C(O)O—(C₁-C₆)alkyl, —C(O)O—CH₂-aryl, —C(O)O-aryl, —NH₂,—NH—(C₁-C₆)alkyl, —NHC(O)—(C₁-C₆)alkyl, —NHC(O)-aryl, —CONH₂,—SO₂aryl(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl or —COR⁸;

R⁸ is an amino acid which is linked through its nitrogen atom;

Z═O, CH₂ or NH;

R⁴ is selected from P, Q or T

R⁹ is selected from —OH, —O-alkyl, —OSO3H, halogen, —C(O)O—(C₁-C₆)alkyl,—C(O)NHR⁸, —OC(O)—(C₁-C₆)alkyl, —O-perhaloalkyl, —OC(O)O—(C₁-C₆)alkyl,—CONR⁵, —NHCO—(C₁-C₆)alkyl, —NHC(O)—O—(C₁-C₆)alkyl, —NHC(O)—O-aryl,—NHSO₂—(C₁-C₆)alkyl, —NHSO₂-aryl, —NHCONR⁵ or;

R¹⁰ is selected from H, Halogen, (C₁-C₆)alkyl, alkoxy, aryloxy,—NHCO—(C₁-C₆)alkyl, —NHSO2-(C₁-C₆)alkyl or —NH—SO₂-aryl;

R¹¹ is —CO(C₁-C₆)alkyl, —SO2-(C₁-C₆)alkyl or —SO₂-aryl;

G′ is selected from H, halogen or (C₁-C₆)alkyl;

G″ is selected from hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl,halogen, perhaloalkyl, CN, CHO, —(C₁-C₃)alkylaryl,—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl, —CH₂R⁹, —CH₂aryl, —CH₂NR⁵, —COOH,—C(O)O(C₁-C₆)alkyl, —CONH—(C₁-C₆)alkyl, —CONR⁵, —SO₂NR⁵,—SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl; n may be one or two;

including their pharmaceutically acceptable salts and their hydrates,solvates, atropisomers, regioisomers, enantiomers, diastereomers,tautomers, polymorphs and prodrugs thereof with a proviso that;

when R⁴ is Q then

R² is other than R⁶ and R⁷;

In another embodiment, the present invention pertains to a compound asabove, however only including pharmaceutically acceptable salts thereof.

In another embodiment, the present invention includes use of compound offormula (IA) for treating disease condition associated withinappropriate thyroid hormone activity selected from obesity, insulinresistance, dyslipidemia, metabolic syndrome, type II diabetes,replacement therapy in elderly subjects with hypothyroidism, depression,cardiovascular diseases and skin disorders by administering atherapeutically effective amount of a compound in a living mammalianorganism, including human being:

Wherein, R¹ and R³ is same or different, and is independently selectedfrom H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, halo, CN, CF₃, —O—(C₁-C₆)alkyl,—CO₂—(C₁-C₆)alkyl, COOH, —CONH—(C₁-C₆)alkyl, —CONH-aryl, —NH2, —CONH—R⁶,—CONR⁵, —C₁-C₃alkyl-aryl, —(C₁-C₃)alkyl-R⁶, —NH—(C₁-C₆)alkyl, —NHaryl,—NH—SO₂—(C₁-C₆)alkyl, —CH₂—NH—(C₁-C₆)alkyl, —CH₂—O—(C₁-C₆)alkyl,—C₁-C₃alkyl-NR⁵, R⁶, R⁷, wherein C₁-C₆alkyl and C₃-C₇ cycloalkyl isoptionally substituted with one or more substituents selected from(C₁-C₆)alkyl, halo, cyano, —OH, oxo, —COOH, —O—(C₁-C₆)alkyl, —O-benzyl,—COO—(C₁-C₆)alkyl, —CONH—(C₁-C₆)alkyl, —CONR⁵, —CONH-aryl,—CONH-heteroaryl or —CH₂NR⁵;

R² is selected from (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)alkenyl,(C₃-C₆)alkynyl, —C(O)—(C₁-C₃)alkyl-COOH, —(C₁-C₃)alkyl-COOH,—C(O)—(C₁-C₃)alkyl-COO-alkyl, —C(O)—C(O)O—(C₁-C₆)alkyl,—C(O)—(C₁-C₃)alkyl-NH—(C₁-C₆)alkyl, —C(O)—O—(C₁-C₆)alkyl, —C(O)NR⁵,—C(O)NH—(C₁-C₆)alkyl, —C(O)—(C₁-C₃)alkylaryl, —C(O)—(C₁-C₃)alkyl-R⁶, R⁶,R⁷, wherein said (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)alkenyl,(C₃-C₆)alkynyl being optionally substituted with one or moresubstituents selected from perhaloalkyl, Oxo, —C(O)OH,—C(O)—O—(C₁-C₃)alkyl, —C(O)—O—(C₁-C₃)alky-laryl,—C(O)—O—(C₁-C₃)alkyl-R⁶, —CONH2, —CONH(C₁-C₃)alkyl, —C(O)NH-aryl,—C(O)NH—R⁶, —CONR⁵—CONHNH₂, —C(═NH)NH—(C₁-C₆)alkyl, —C(═NH)NH₂,C(═NH)NHOH, —C(O)—R⁸, —C(O)NHSO₂(C₁-C₆)alkyl, —C(O)NHSO₂-aryl,—C(O)NHOH, —C(O)NHSO₂—R⁶, —C(O)NHNH—(C₁-C₆)alkyl, —C(O)NHNH-aryl,—CONH—(C₁-C₂)alkyl-aryl, —C(O)NH—(C₁-C₂)alkyl-R⁶, —CH₂NR⁵, —NH₂,—NH—(C₁-C₆)alkyl, —NH—C(O)—O—(C₁-C₃)alkyl, —NH—C(O)—(C₁-C₃)alkyl,—NHC(O)-aryl, —NHC(O)—(C₁-C₃)alkylaryl, —NHC(O)—R⁶, —NH—C(O)NR⁵,—NH—C(O)NH-aryl, —NHC(O)NH—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl,—NH—SO₂-aryl, —NH—SO₂—R⁶, halo, cyano, —OH, —O—(C₁-C₆)alkyl, —O-aryl,—O-heteroaryl, —O—(C₁-C₂)alkyl-aryl, —SO₃H, —SO₂NH-aryl, —SO₂NH—R⁶ or—SO₂NH—(C₁-C₆)alkyl, R⁶ or R⁷;

R⁵ together with Nitrogen atom to which it is attached form a saturatedor unsaturated (C₃-C₆) membered ring, which may further contain 1-2heteroatoms selected from O, N or S and which may be optionallysubstituted with one or more substituents selected from oxo, —COOH,halo, —OH, —O—(C₁-C₆)alkyl, or —(C₁-C₆)alkyl;

R⁶ is selected from phenyl or 5-8 membered heteroaryl containing 1-4heteroatoms selected from O, N or S, wherein said heteroaryl or phenylring being optionally substituted with one or more substituents selectedfrom halogen, —OH, —O—(C₁-C₆)alkyl, -perhaloalkyl, —(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl, —SO₂(C₁-C₆)alkyl, cyano, —COOH, —C(O)O—(C₁-C₆)alkyl,—C(O)O—CH₂-aryl, —C(O)O-aryl, —CONH(C₁-C₃)alkyl, nitro, —NH₂,—NH—(C₁-C₆)alkyl, —NHC(O)— (C₁-C₆)alkyl, —NHC(O)-aryl,—NHSO₂(C₁-C₆)alkyl, —CONH₂, —SO₂—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl or—COR⁸;

R⁷ is a 3-6 membered heterocyclic ring containing 1-4 heteroatomselected from O, N or S, and the said heterocyclic ring being optionallysubstituted with one or more substituents selected from oxo, halogen,—O—(C₁-C₆)alkyl, —OH, —CF₃, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano,—COOH, —C(O)O—(C₁-C₆)alkyl, —C(O)O—CH₂-aryl, —C(O)O-aryl, —NH₂,—NH—(C₁-C₆)alkyl, —NHC(O)—(C₁-C₆)alkyl, —NHC(O)-aryl, —CONH₂,—SO₂aryl(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl or —COR⁸;

R⁸ is an amino acid which is linked through its nitrogen atom;

Z═O, CH₂ or NH;

R⁴ is selected from P, Q or T

R⁹ is selected from —OH, —O-alkyl, —OSO3H, halogen, —C(O)O—(C₁-C₆)alkyl,—C(O)NHR⁸, —OC(O)—(C₁-C₆)alkyl, —O-perhaloalkyl, —OC(O)O—(C₁-C₆)alkyl,—CONR⁵, —NHCO—(C₁-C₆)alkyl, —NHC(O)—O—(C₁-C₆)alkyl, —NHC(O)—O-aryl,—NHSO₂—(C₁-C₆)alkyl, —NHSO₂-aryl, —NHCONR⁵ or;

R¹⁰ is selected from H, Halogen, (C₁-C₆)alkyl, alkoxy, aryloxy,—NHCO—(C₁-C₆)alkyl, —NHSO₂—(C₁-C₆)alkyl or —NH—SO₂-aryl;

R¹¹ is H, (C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl or —SO₂-aryl;

G′ is selected from H, halogen or (C₁-C₆)alkyl;

G″ is selected from hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl,halogen, perhaloalkyl, CN, CHO, —(C₁-C₃)alkylaryl,—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl, —CH₂R⁹, —CH₂aryl, —CH₂NR⁵, —COOH,—C(O)O(C₁-C₆)alkyl, —CONH—(C₁-C₆)alkyl, —CONR⁵, —SO₂NR⁵,—SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl; n may be one or two;

including their pharmaceutically acceptable salts and their hydrates,solvates, atropisomers, regioisomers, enantiomers, diastereomers,tautomers, polymorphs and prodrugs thereof.

In another embodiment, the present invention includes syntheticintermediates that are useful in preparing the compounds of formula (I)and process for preparing such intermediates.

Another embodiment of the present invention is a method for preparationof a compound of formula (I) as herein described in Scheme 1, 2 and 3.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising a compound of formula (I), optionally inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.

Another embodiment of the present invention is a method for treatingobesity by administering a compound of formula (I) to a mammal in needthereof.

Another embodiment of the present invention is a method for amelioratinginsulin resistance and/or preventing or delaying progression to frankdiabetes by administering a compound of formula (I) to a mammal in needthereof.

Another embodiment of the present invention is a method for preventingand treating dyslipidemia by administering a compound of formula (I) toa mammal in need thereof.

Another embodiment of the present invention is a method for preventingand treating metabolic syndrome by administering a compound of formula(I) to a mammal in need thereof.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for treating obesity.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for ameliorating insulinresistance and/or preventing or delaying progression to frank diabetes.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for preventing andtreating dyslipidemia.

Another embodiment of the present invention is the use of a compound offormula (I) for the preparation of a medicament for preventing andtreating metabolic syndrome.

In still another embodiment, the present invention provides method oftreating disease condition associated with inappropriate thyroid hormoneactivity without significantly affecting the appetite by administering atherapeutically effective amount of thyroid like compound.

In still another embodiment, the present invention provides method oftreating disease condition associated with inappropriate thyroid hormoneactivity without significantly affecting the appetite by administeringthe therapeutically effective amount of compound of formula (IA).

DETAIL DESCRIPTION OF THE INVENTION Definitions

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

The term “Thyroid like compound(s)” as used herein denotes compoundsstructurally similar to diiodothyronine which are likely to act in amanner similar to that of thyroid hormone but significantly devoid ofthe toxic effects of Thyroid Hormone.

The term “thyroid receptor ligand” or “thyroid ligand” as used hereincovers any chemical substance which can bind to a thyroid receptor. Theligand may act as an antagonist, an agonist, a partial antagonist or apartial agonist.

The term “thyroid receptor” as used herein represents a molecule thatreceives a thyroid hormone and permits it to dock on the nucleus of acell and that functions as hormone-activated transcription factor andact by modulating the expression of genes. THRs bind DNA in the absenceof hormone, usually suppressing the transcription of genes. Hormonebinding involves a conformational change in the receptor that lets it toactivate transcription.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext.

The term “compound” employed herein refers to any compound encompassedby the generic formula disclosed herein. The compounds described hereinmay contain one or more double bonds and therefore, may exist asstereoisomers, such as double-bond isomers (i.e., geometric isomers).Accordingly, the chemical structures depicted herein encompass allpossible stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure) andstereoisomeric mixtures. The compounds may also exist in severaltautomeric forms including the enol form, the keto form and mixturesthereof. Accordingly, the chemical structures

depicted herein encompass all possible tautomeric forms of theillustrated compounds. The compounds described also include isotopicallylabeled compounds where one or more atoms have an atomic mass differentfrom the atomic mass conventionally found in nature. Examples ofisotopes that may be incorporated into the compounds of the inventioninclude, but are not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O.Compounds may exist in unsolvated forms as well as solvated forms,including hydrated forms. In general, compounds may be hydrated orsolvated. Certain compounds may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated herein and are intended to be within the scope of thepresent invention.

The term “regioisomer” is a term known to those skilled in the art andis defined in text books such as Organic Synthesis, Smith, M., (McGrawHill), which defines a regioisomer as “two or more molecules with thesame empirical formula, but with a different attachment of the atoms(different connectivity)”.

The term “atropisomer” as used herein refers to a stereoisomer where theelement of chirality is located on a molecular plane or axis.

Further, it should be understood, when partial structures of thecompounds are illustrated, a dash (“-”) or “*” indicate the point ofattachment of the partial structure to the rest of the molecule. Thenomenclature of the compounds of the present invention as indicatedherein is according to MDL ISIS® Draw Version 2.2.

“Pharmaceutically acceptable salts” includes derivatives of thedisclosed compounds, wherein the parent compound is modified by makingnon-toxic acid or base addition salts thereof, and further refers topharmaceutically acceptable solvates, including hydrates, of suchcompounds and such salts. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid addition saltsof basic residues such as amines; alkali or organic addition salts ofacidic residues such as carboxylic acids; and the like, and combinationscomprising one or more of the foregoing salts. The pharmaceuticallyacceptable salts include non-toxic salts and the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, non-toxic acid salts includethose derived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; other acceptableinorganic salts include metal salts such as sodium salt, potassium salt,cesium salt, and the like; and alkaline earth metal salts, such ascalcium salt, magnesium salt, and the like, and combinations comprisingone or more of the foregoing salts. Pharmaceutically acceptable organicsalts includes salts prepared from organic acids such as acetic,trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC—(CH₂)_(n)—COOH where n is 0-4, andthe like; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, and the like;and amino acid salts such as arginate, asparginate, glutamate, and thelike; and combinations comprising one or more of the foregoing salts.

The term “alkyl”, used either alone or in attachment with another grouprefers to a saturated aliphatic hydrocarbon radical having the indicatednumber of carbon atoms and that is unsubstituted or optionallysubstituted. When a subscript is used with reference to an alkyl orother group, the subscript refers to the number of carbon atoms thatgroup may contain. For example, a “C₁-C₆ alkyl” would refer to any alkylgroup containing one to six carbons in the structure. Alkyl may be astraight chain or a branched chain.

The term “alkenyl”, used either alone or in attachment with anothergroup refers to an unsaturated (=) aliphatic hydrocarbon radical havingthe indicated number of carbon atoms and that is unsubstituted oroptionally substituted. When a subscript is used with reference to analkyl or other group, the subscript refers to the number of carbon atomsthat group may contain. For example, a “C₃-C₆ alkenyl” would refer toany alkenyl group containing three to six carbons in the structure.Alkenyl may be a straight chain or a branched chain.

The term “alkynyl”, used either alone or in attachment with anothergroup refers to an unsaturated(≡) aliphatic hydrocarbon radical havingthe indicated number of carbon atoms and that is unsubstituted oroptionally substituted. When a subscript is used with reference to analkyl or other group, the subscript refers to the number of carbon atomsthat group may contain. For example, a “C₃-C₆ alkynyl” would refer toany alkenyl group containing three to six carbons in the structure.Alkynyl may be a straight chain or a branched chain.

The “cycloalkyl” refers to a saturated aliphatic hydrocarbon radicalhaving the indicated number of carbon atoms and that is unsubstituted oroptionally substituted. When a subscript is used with reference to analkyl or other group, the subscript refers to the number of carbon atomsthat group may contain. For example, a “C₃-C₆ cycloalkyl” would refer toany cycloalkyl group containing three to six carbons in the structure.

The term “aryl” refers to an aromatic group for example, which is a 6 to10 membered monocyclic or bicyclic ring system, which may beunsubstituted or substituted. Representative aryl groups may be phenyl,naphthyl and the like. When said ring is substituted, the substituentsare selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkoxy, nitro,carboxylic acid, CF3, NHSO2alkyl, NHCOalkyl, alkyl, alkenyl, alkynyl,cycloalkyl and acyl.

The term “heteroaryl” as used herein, refers to an aromatic group forexample, which is a 5 to 10 membered monocyclic or bicyclic ring system,which has at least one heteroatom and at least one carbon atomcontaining ring. The heteroaryl group may be attached at any availablenitrogen or carbon atom of any ring. Exemplary monocyclic heteroarylgroups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,oxadiazolyl, tetrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl and the like. Exemplary bicyclic heteroarylgroups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl,benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl and the like.

The “alkoxy” refers to an alkyl group as defined above attached to theparent molecular moiety through an oxygen bridge. Representative alkoxyradicals include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy,n-hexyloxy, sec-butoxy, tert-butoxy, tert-pentyloxy, and the like.

As used herein, the term “halo” or “halogen” denotes a fluoro, chloro,bromo, or iodo group.

All substituents (R¹, R² . . . ) and their further substituentsdescribed herein may be attached to the main structure at any heteroatomor carbon atom which results in formation of stable compound.

As used herein, the term “mammal” means a human or an animal such asmonkeys, primates, dogs, cats, horses, cows, etc.

As used herein, the term “polymorphs” pertains to compounds having thesame chemical formula, the same salt type and having the same form ofhydrate/solvate but having different crystallographic properties.

As used herein, the term “hydrates” pertains to a compound having anumber of water molecules bonded to the molecule.

As used herein, the term “solvates” pertains to a compound having anumber of solvent molecules bonded to the molecule.

The present invention also encompasses prodrugs of compounds of theinvention, i.e. second compounds which are converted to the firstcompounds in vivo.

In vivo cleavable esters are just one type of prodrug of the parentmolecule. An in vivo hydrolysable (or cleavable) ester of a compound ofthe present invention that contains a carboxy group is, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid. Suitable pharmaceuticallyacceptable esters for carboxy include C₁-C₈ alkoxymethyl esters, forexample, methoxymethyl, C₁-C₈ alkanoloxymethyl ester, for example,pivaloyloxymethyl; phthalidyl esters; C₃-C₈ cycloalkoxycarbonyloxy-C₁-C₈alkyl esters, for example, 1-cyclohexylcarbonyloxyethyl;1,3-dioxolen-2-onylmethyl esters, for example,5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₈ alkoxycarbonyloxyethylesters, for example, 1-methoxycarbonyloxymethyl; and may be formed atany carboxy group in the compounds of the present invention.

In the context of the present specification, the term “treat” or“treatment” also includes “prophylaxis” unless there are specificindications to the contrary. The term “treat” or “treatment” within thecontext of the present invention further encompasses to administer atherapeutically effective amount of a compound of the present invention,to mitigate either a pre-existing disease state, acute or chronic, or arecurring condition. This definition also encompasses prophylactictherapies for prevention of recurring condition and continued therapyfor chronic disorders.

The phrase “a therapeutically effective amount” means the amount of acompound that, when administered to a patient for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,mode of administration, the disease and its severity and the age,weight, etc., of the patient to be treated.

When used, the expressions “comprise” and “comprising” denote “include”and “including” but not limited to. Thus, other ingredients, carriersand additives may be present.

In one embodiment, the present invention provides a compound of formula(I)

Wherein, R¹, R², R³, Z and R⁴ is as defined above.

The invention also provides pharmaceutically acceptable salts and theirhydrates, solvates, atropisomers, regioisomers, enantiomers,diastereomers, tautomers, polymorphs and prodrugs thereof.

One of the preferred embodiment of the present invention is a compoundof formula (I) mentioned above, wherein R¹, R², R³ and Z is as definedabove and R⁴ is selected from P or T.

Pharmaceutical Composition

In another embodiment of the invention there is provided apharmaceutical composition comprising a therapeutically effective amountof one or more of a compound of formula (I). While it is possible toadminister therapeutically effective quantity of compounds of formula(I) either individually or in combination, directly without anyformulation, it is common practice to administer the compounds in theform of pharmaceutical dosage forms comprising pharmaceuticallyacceptable excipient(s) and at least one active ingredient. These dosageforms may be administered by a variety of routes including oral,topical, transdermal, subcutaneous, intramuscular, intravenous,intranasal, pulmonary etc.

Oral compositions may be in the form of solid or liquid dosage form.Solid dosage form may comprise pellets, pouches, sachets or discreteunits such as tablets, multi-particulate units, capsules (soft & hardgelatin) etc. Liquid dosage forms may be in the form of elixirs,suspensions, emulsions, solutions, syrups etc. Composition intended fororal use may be prepared according to any method known in the art forthe manufacture of the composition and such pharmaceutical compositionsmay contain in addition to active ingredients, excipients such asdiluents, disintegrating agents, binders, solubilizers, lubricants,glidants, surfactants, suspending agents, emulsifiers, chelating agents,stabilizers, flavours, sweeteners, colours etc. Some example of suitableexcipients include lactose, cellulose and its derivatives such asmicrocrystalline cellulose, methylcelulose, hydroxy propyl methylcellulose, ethylcellylose, dicalcium phosphate, mannitol, starch,gelatin, polyvinyl pyrolidone, various gums like acacia, tragacanth,xanthan, alginates & its derivatives, sorbitol, dextrose, xylitol,magnesium Stearate, talc, colloidal silicon dioxide, mineral oil,glyceryl mono Stearate, glyceryl behenate, sodium starch glycolate,Cross Povidone, crosslinked carboxymethylcellulose, various emulsifierssuch as polyethylene glycol, sorbitol fatty acid, esters, polyethyleneglycol alkylethers, sugar esters, polyoxyethylene polyoxypropyl blockcopolymers, polyethoxylated fatty acid monoesters, diesters and mixturesthereof.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection,N-Methyl-2-Pyrrolidone, propylene glycol and other glycols, alcohols, anaturally occurring vegetable oil like sesame oil, coconut oil, peanutoil, cotton seed oil or a synthetic fatty vehicle like ethyl oleate orthe like. Buffers, anti-oxidants, preservatives, complexing agents likecellulose derivatives, peptides, polypeptides and cyclodextrins and thelike can be incorporated as required, The dosage form can have a slow,delayed or controlled release of active ingredients in addition toimmediate release dosage forms.

The amount of active ingredient which is required to achieve atherapeutic effect will, of course, vary with the particular compound,the route of administration, the subject under treatment, and theparticular disorder or disease being treated. The compounds of theinvention may be administered orally or parenterally at a dose of from0.001 to 1500 mg/kg per day, preferably from 0.01 to 1500 mg/kg per day,more preferably from 0.1 to 1500 mg/kg per day, most preferably from 0.1to 500 mg/kg per day. The dose range for adult humans is generally from5 mg to 35 g per day and preferably 5 mg to 2 g per day. Tablets orother dosage forms of presentation provided in discrete units mayconveniently contain an amount of compound of the invention which iseffective at such dosage or as a multiple of the same, for example unitscontaining 5 mg to 500 mg.

Whilst a compound of the invention may be used as the sole activeingredient in a medicament, it is also possible for the compound to beused in combination with one or more further active agents. Such furtheractive agents may be further compounds according to the invention, orthey may be different therapeutic agents, for example an anti-obesity oranti-dyslipidemic agent or other pharmaceutically active agent.

The compounds of the present invention may be employed in combinationwith one or more other suitable therapeutic agents selected from thegroup consisting of hypolipidemic agents, anti-atherosclerotic agents,anti-diabetic agents, anti-osteoporosis agents, anti-obesity agents,anti-anxiety agents, anti-depressants, anti-hypertensive agents, cardiacglycosides, appetite suppressants, growth promoting agents, agents forthe treatment of skin disorders, bone resorption inhibitors and thyroidmimetics.

Examples of suitable hypolipidemic agents for use in combination withthe compounds of the present invention include but not limited to an MTPinhibitor, a HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fibric acid derivative, an ACAT inhibitor, lipoxygenaseinhibitors, a cholesterol absorption inhibitor, an ileal Na+/bile acidcotransporter inhibitor, upregulators of LDL receptor, a cholesterylester transfer protein (CETP) inhibitor, a bile acid sequestrant, aperoxisome proliferator-activator receptor (PPAR)-alpha agonist, aperoxisome proliferator-activator receptor (PPAR)-delta agonist, aperoxisome proliferator-activator receptor (PPAR)-gamma/delta dualagonist, a peroxisome proliferator-activator receptor (PPAR)-alpha/deltadual agonist and/or a nicotinic acid and its derivative, or apharmaceutically acceptable salt thereof.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include but not limited to abiguanide such as metformin, phenformin, a sulfonylurea such asgliclazide, an alpha glucosidase inhibitor, a PPARγ agonist such asthiazolidinediones, a PPARα agonist such as fibric acid derivatives, analpha-amylase inhibitor, a fatty acid oxidation inhibitor, an A2antagonist, a PPARδ agonist or antagonist, a PPARα/γ dual agonist, anaP2 inhibitor, a dipeptidyl peptidase IV (DP4) inhibitor, a SGLT2inhibitor, a glycogen phosphorylase inhibitor, a glucagon-like peptide-1(GLP-1) and its analogues, a glucokinase activator, a VPAC2 receptoragonist, a PTP-1B (protein tyrosine phosphatase-1B) inhibitor, an11β-HSD 1 (11β-hydroxy-steroid dehydrogenase1) inhibitor, meglitinide,glucocorticoid (GR) antagonist as well as insulin, or a pharmaceuticallyacceptable salt thereof.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include but not limited toalendronate, risedronate, PTH, PTH fragment, raloxifene, calcitonin,RANK ligand antagonists, calcium sensing receptor antagonists, TRAPinhibitors, selective estrogen receptor modulators (SERM) and AP-1inhibitors or a pharmaceutically acceptable salt thereof.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include but not limited to a 5HT(serotonin) transporter inhibitor, a NE (norepinephrine) transporterinhibitor, a CB-1 (cannabinoind-1 receptor) antagonist/inverse agonist,a ghrelin antagonist, a H3 (histamine H3) antagonist/inverse agonist, aNPY1 (neuropeptide Y Y1) antagonist, a NPY2 (neuropeptide Y Y2) agonist,a NPY5 (neuropeptide Y Y5) antagonist, a leptin or its derivative, anopioid antagonist, an orexin antagonist, a BRS3 (bombesin receptorsubtype 3) agonist, a CCK-A (cholecystokinin-A) agonist, a CNTF (ciliaryneurotrophic factor), a CNTF derivative, a GHS (growth hormonesecretagogue receptor) agonist, 5HT2c (serotonin receptor 2c) agonist, aMc3r (melanocortin 3 receptor) agonist, a Mc4r (melanocortin 4 receptor)agonist, a monoamine reuptake inhibitor, a β3 (beta adrenergic receptor3) agonist, a DGAT1 (diacylglycerol acyltransferase 1) inhibitor, aDGAT2 (diacylglycerol acyltransferase 2) inhibitor, a FAS (fatty acidsynthase) inhibitor, a PDE (phosphodiesterase) inhibitor, a thyroidhormone β agonist, an UCP-1 (uncoupling protein 1), 2, or 3 activator, aglucocorticoid antagonist, a SCD-1 (stearoyl-CoA desaturase-1)inhibitor, a lipase inhibitor, a fatty acid transporter inhibitor, adicarboxylate transporter inhibitor, an anorectic agent, such asdexamphetamine, phentermine, phenylpropanolamine or mazindol or apharmaceutically acceptable salt thereof.

The compounds of the present invention may be combined with growthpromoting agents, such as, but not limited to, TRH, diethylstilbesterol,theophylline, enkephalins, E series prostaglandins or a pharmaceuticallyacceptable salt thereof.

The compounds of the present invention may also be used in combinationwith growth hormone secretagogues such as GHRP-6, GHRP-1, GHRP-2 or withgrowth hormone releasing factor and its analogs or growth hormone andits analogs or somatomedins including IGF-1 and IGF-2, or withalpha-adrenergic agonists, such as clonidine or serotinin 5-HT.sub.Dagonists, such as sumatriptan, or agents which inhibit somatostatin orits release, such as physostigmine and pyridostigmine. A still furtheruse of the disclosed compounds of the invention is in combination withparathyroid hormone, PTH(1-34) or bisphosphonates, such as MK-217(alendronate).

Examples of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, oxazepam, and hydroxyzine pamoate and the like.

Examples of suitable anti-depressants for use in combination with thecompounds of the present invention include citalopram, fluoxetine,nefazodone, sertraline, paroxetine and the like.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include but not limited toan angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, abeta adrenergic receptor blocker, an alpha adrenergic receptor blocker,a calcium channel blocker, a potassium channel activator, an aldosteronesynthase inhibitor, a neutral endopeptidase (NEP) inhibitor, a dualangiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor,an endothelin receptor antagonist, a dual angiotensin and endothelinreceptor antagonist (DARA), a diuretic or a pharmaceutically acceptablesalt thereof.

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable thyroid mimetics for use in combination with thecompounds of the present invention include but not limited to KB-2115,MB07811 or pharmaceutically acceptable salt thereof.

For the treatment of skin disorders or diseases as described above, thecompounds of the present invention may be used alone or optionally incombination with a retinoid, such as tretinoin, or a vitamin D analog.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Where the compounds of the invention are administered in form ofcombination with one or more other therapeutic agent(s), it can beadministered either concurrently, sequentially or in a fixed unit dosageform.

Abbreviations

TSH—Thyroid-stimulating hormone also known as thyrotropin,

T4—Thyroxine,

T3—Triiodothyronine,

T2—Diiodothyronine,

rT3—Reverse T3,

SAR—Structure activity relationship,

NPY—Neuropeptide Y.

Reaction Schemes for the Synthesis of Compounds of the Invention

In the following, reaction schemes are given for synthesis of thecompounds according to another embodiment of the present invention.

Wherein R¹, R², R³, R⁴, and Z are as defined above and Y is halo or anyother leaving group.

In a specific embodiment, the compounds of formula (I) is obtained fromthe pyrazole derivatives of formula (II) or diketo derivatives offormula (III) as shown in scheme-1.

The derivatives of formula (II), is reacted with substituted alkylhalide or any other alkylderivative containing a suitable leaving groupin presence of a base selected from metal hydride or metal carbonate, inpolar aprotic solvent such as tetrahydrofuran to yield the compounds offormula (I).

Similarly, the diketo derivative of formula (III) on reacting withsubstituted hydrazine derivatives in alcoholic solvent, yield thecompound of formula (I).

The compounds of formula (II) is obtained by treating the compounds offormula (III) as shown in Scheme 1, with hydrazine hydrate under theknown condition in the literature. The compound of formula (III) isprepared from the compound of formula (IV) by reacting it withsubstituted hydroxy indanes of formula (XII), (XIV), (XVI), or (XVII) orwith substituted hydroxyl indoles in the presence of base such as metalhydride or metal carbonate in a polar aprotic solvent such astetrahydrofuran. The compounds of formula (IV) can be obtained fromdiketo derivative of the formula (V) by dissolving it in an appropriatesolvent such as acetonitrile in the presence of a suitable reagent, liketrimethylsilyl chloride and dimethylsulphoxide.

Alternately, the compounds of formula (III) is directly obtained byreacting the compounds of formula (V) either with aldehyde derivativesof formula (XIII) in presence of piperidine-acetic acid followed byhydrogenation in presence of catalyst such as Pd/BaSO4 under hydrogenatmosphere or with chloro derivative of formula (XV) in presence ofmetal hydride or metal carbonate.

In an alternate process, the compound of formula (III) can also beprepared from the compound of formula (VI) by reacting it withappropriate acid chloride or ethyl ester in presence of a base such asmetal hydride or metal alkoxide. The compound of formula (VI) isobtained from the compound of formula (VII) by reacting it with suitablehydroxy or amino indane of formula (XII), (XIV), (XVI), or (XVII) orindole derivatives in presence of a base preferably selected from metalhydride or metal carbonate. The compound of formula (VII), as shown inscheme 1 is obtained by bromination of methyl ketone of formula (VIII)in an appropriate solvent such as methanol.

The compounds of formula (II) and the formula (I) can be prepared eitherfrom keto derivative of formula (IX) or from cyano derivative of formula(X). By reacting the compounds of formula (IX) with an appropriatesubstituted or unsubstituted hydrazine in presence of alcoholic solventto gave compounds of formula (I) and formula (II) respectively. Thecompound of formula (IX) is obtained by reacting the compound of formula(VI) with dimethylformamide diethyl acetal.

Alternatively, the compounds of formula (X) is reacted with compounds offormula (XV) in presence of a base such as metal hydride, followed bytreatment with appropriate substituted or unsubstituted hydrazine inpresence of alcoholic solvent to obtain compounds of formula (I) andformula (II) respectively

As shown in scheme 1, the cyano derivative of formula (X) is obtainedfrom the compound of formula (VII) by dissolving it in an organicsolvent such as dimethyl formamide, in the presence of sodium cyanide.The compound of formula (I) as obtained as per the scheme 1 are eitherfinal compounds or else can be converted to formula (I) by appropriatefunctional group conversion or using conventional methods known in theart.

The intermediates of formula (XII), (XIII), (XIV) and (XV) can beobtained as shown in scheme 2 as depicted herein below.

As shown in scheme-2, the intermediates (XII) is obtained fromsubstituted dihydrocoumarin XI or from 4-hydroxyindane. In a specificembodiment, the substituted dihydrocoumarins of formula (XI), is heatedwith aluminum trichloride, followed by reducing the keto group ofindanone with triethylsilane in trifluoroacetic acid to obtain thecompound of formula (XII). The reduction of indanone can also be carriedout as method disclosed in US2005/0037925, WO9943647 and US2002/0040016.Alternately, 4-hydroxyindane is reacted with paraformaldehyde to obtainthe aldehyde substituted compound, which is either reduced to methylgroup, in presence of suitable agent such as NH2NH2-KOH-Ethylene glycolor Pd/C under hydrogen atmosphere or to an acid by oxidizing thealdehyde using the mild oxidizing agent such as sulfamic acid and sodiumchlorite. The acid group thus, obtained, further reacted with anappropriate alcohol in the presence of mineral acid to obtain ester orusing suitable amine and coupling reagent selected from carbodiimide toobtain amide. Further the aldehyde group of formula (XII) is also usedto obtain the cyano derivative by using the conventional method. Inanother alternate process, the halogen substituted hydroxyindanederivatives of formula (XII) is also prepared by reacting4-hydroxyindane with N-halosuccinimide in presence of catalytic amountof diisopropylamine in solvents preferably tetrahydrofuran ordihaloalkane (G″=halogen) or by treatment of sulfuryl chloride.(G″=chloro).

Compound of formula (XII) or 4-hydroxy indane (G″=H) is treated withhexamine in trifluoroacetic acid, to obtain the compound of formula(XIII).

In still another specific embodiment, compound of formula (XV) can beobtained from the compound of formula (XIII) by reacting it with methyliodide in presence of a base followed by reduction in presence of areducing agent such as sodium borohydride and further reacting theintermediate so obtained with carbon tetrabromide and triphenylphosphine or thionyl chloride respectively. In an alternate process, thecompound of formula (XIV) is also obtained from the compound of formula(XII) or 4-hydroxy indane by treating it with nitric acid in presence ofacetic acid.

The intermediates of formula (XVI) and (XVII) can be obtained as shownin scheme 3 as depicted herein below.

The intermediate of formula (XVI) is obtained from the dimethoxyindanone, by reducing the keto group of indanone, using triethylsilaneor Pd—C, followed by reacting with boron tribromide.

For the compound of formula (XVII) when G″=methyl is obtained bytreating 7-methoxy-indan-4-ol (XVI) with paraformaldehyde and thenreducing the intermediate by catalyst reducing agent such as Pd/C, underhydrogen atmosphere, in the presence of a suitable alcoholic solventselected from methanol. Alternately, for the compound of formula (XVII)when G″=ester or amide, the compounds of formula (XVI) is reacted withparaformaldehyde which on further oxidation under mild condition asdescribed herein above can be converted to G″=acid. Further the acidgroup can be reacted with an appropriate alcohol in the presence ofmineral acid to obtain ester or with using suitable amine and couplingreagent selected from carbodiimide to obtain amide. For G″=cyano informula (XVII) can be obtained by appropriately selecting cyanosubstituted indanone or by converting amide derivative to cyano usingconventional method.

Alternately, the halo substituted compound of formula (XVII) is obtainedby reacting the 7-methoxy-indan-4-ol (XVI) with N-halosuccinimide inpresence of catalytic amount of diisopropylamine in solvents selectedfrom tetrahydrofuran or by treatment of sulfuryl chloride (G″=Cl).

PREPARATORY EXAMPLES

The present invention is further illustrated by the followingnon-limiting Examples.

The examples illustrate the preparation of the compounds of formula (I)and as such are not to be considered or construed as limiting the scopeof the invention set forth in the claims appended thereto.

Example-1 Compound No. 13-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]propionic acidStep I: Preparation of 4,7-Dimethoxy indane

To the cooled and stirred suspension of 4,7-Dimethoxyindan-1-one (35 gm,0.182 mole) in Triethyl silane (105.7 gm, 0.909 mole), addedTrifluoroacetic acid (350 ml) at 10-15° C. The stirring was continued atroom temperature for 2 hours and quenched into the water. It wasextracted with Ethyl acetate. The Ethyl acetate layer was washed withSodium bicarbonate solution, dried over Sodium sulphate and evaporatedto give crude mass which was purified by column chouromatography using5% Ethyl acetate in hexane (22.5 gm).

Yield: 69.3%

¹H-NMR (400 MHz, CDCl₃): δ 6.67 (2H, s), 3.70 (6H, s), 2.74-2.78 (4H,m), 1.95-2.02 (2H, m)

Step-II: Preparation of 7-methoxyindan-4-ol

To the clear solution of 4,7-Dimethoxyindane (22.5 gm, 0.126 mole) inMethylene chloride (400 ml), added Boron tribromide (12.27 ml, 0.13mole) at 0° C. After 2 hours stirring at 0-10° C., water (100 ml) wasadded and then the reaction mixture was extracted with Methylenechloride. The Methylene chloride layer was dried over Sodium sulphateand distilled off to give a crude mass which was purified by columnchromatography using 7% Ethyl acetate in Hexane (9.0 gm).

Yield: 43.4%

¹H-NMR (400 MHz, DMSO-d₆): δ 8.66 (1H, s), 6.493-6.558 (2H, m), 3.66(3H, s), 2.71-2.75 (4H, m), 1.92-2.00 (2H, m)

Step-III: Preparation of4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-1H-pyrazole

To the suspension of 60% Sodium hydride (2.0 gm, 0.051 moles) inTetrahydrofuran (20 ml) added a solution of 7-Methoxyindan-4-ol (7.0 gm,0.042 mole) in Tetrahydrofuran (30 ml) at room temperature. After onehour stirring a solution of 3-Chloro 2,4-pentanedione (9.0 ml, 0.075mole) in Tetrahydrofuran (20 ml) was added followed by addition ofPotassium bromide (3.0 gm, 0.025 mole). The reaction mixture was stirredat 70° C. for 6 hours. The water was added and extracted with Diethylether. The Ether layer was separated and distilled off to give an oilymass which was partially purified through a column using 2% Ethylacetate in Hexane to give crude mass (2.7 gm). The obtained crude masswas stirred with Hydrazine hydrate (1 ml) in 20 ml Ethanol at 10° C.Ethanol was evaporated to dryness. The obtained residue was partitionedbetween water and Ethyl acetate. The separated Ethyl acetate layer wasdried over Sodium sulphate and distilled off to give desired product(2.0 gm).

Yield: 18.1% (in two steps)

¹H-NMR (400 MHz, DMSO-d₆): δ 2.12 (1H, s), 6.61 (1H, d), 6.29 (1H, d),3.69 (3H, s), 2.88 (2H, t) 2.80 (2H, t), 2.00-2.07 (5H, m), 1.91 (3H,s).

Step-IV: Preparation of3-[4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionic acidethyl ester

To the suspension of 60% Sodium hydride (0.372 gm 0.0093 mole) in 10 mlTetrahydrofuran, added solution of Pyrazole derivative obtained instep-III (2.0 gm, 0.00775 mole) in 10 ml Tetrahydrofuran under nitrogenatmosphere at room temperature After 1 hour stirring at roomtemperature, a solution of 3-Chloro ethyl propionate (1.15 gm, 0.0084mole) in 10 ml Tetrahydrofuran was added to the reaction mixture It wasstirred at room temperature for 4 hours. The reaction mixture was pouredinto the water, extracted with ethyl acetate. The Ethyl acetate layerwas dried over Sodium sulphate and distilled off. The obtained crudemass was purified by column chromatography using 20% Ethyl acetate inHexane to give the desired product (0.850 gm).

Yield: 30.6

¹H-NMR (400 MHz, DMSO-d₆): δ 6.60 (1H, d), 6.26 (1H, d), 4.15 (2H, t),4.05 (2H, q), 3.69 (3H, s), 2.88 (2H, t), 2.78-2.83 (4H, m), 1.99-2.08(5H, m), 1.89 (3H, s), 1.16 (3H, t).

Step-V: Preparation of3-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionic acid

To the clear solution of Ethyl ester derivative obtained in step-IV(0.85 gm, 0.0023 mole) in 15 ml Methylene chloride, added a solution ofBoron tribromide (1.0 ml, 0.0105 mole) in 15 ml Methylene chloride at 0°C. The reaction mixture was stirred for 2 hours at room temperature; 10ml water was added and extracted with Ethyl acetate. The Ethyl acetatelayer was dried over Sodium sulphate and distilled off to give a solidproduct (230 mg).

Yield: 30.6%

¹H-NMR (400 MHz, DMSO-d₆):): δ 12.27 (1H, bs), 8.77 (1H, bs), 6.42 (1H,d), 6.15 (1H, d), 4.10 (2H, t), 2.84 (2H, t), 2.71-2.78 (4H, m),1.98-2.04 (5H, m), 1.88 (3H, s)

Mass: 315 (M⁺−1)

Example-2 Compound No. 73-[4-(7-Hydroxy-indan-4-yloxy)-3-thiophen-2-yl-pyrazol-1-yl]-propionicacid and3-[4-(7-Hydroxy-indan-4-yloxy)-5-thiophen-2-yl-pyrazol-1-yl]-propionicacid Step-I: Preparation of2-(7-Methoxy-indan-4-yloxy)-1-thiophen-2-yl-ethanone

To the clear solution of 4-Hydroxy-7-methoxy indane (2.0 gm, 0.0121mole) in Acetone (20 ml), Potassium carbonate (2.52 gm, 0.0182 mole) wasadded at room temperature and stirred for 1.5 hours. A solution of2-Bromo-1-thiophene-2-yl-ethanone (3.75 gm, 0.0181 mole) in Acetone (10ml) was added at 0° C. and stirred for 8 hours at room temperature. Thereaction mixture was poured into the water (50 ml) and extracted withEthyl acetate (2×100 ml). The Ethyl acetate layer was dried over Sodiumsulphate and evaporated to give a crude product which was purified bycolumn chromatography using 2% Ethyl acetate in hexane as a mobile phaseThe collected eluent was evaporated to yield desire product (2.1 gm) asan viscous oil.

Yield: 59.8%

¹H-NMR (400 MHz, DMSO-d₆): δ 8.12 (1H, dd), 8.09 (1H, dd), 7.29-7.31(1H, m), 6.63 (2H, s), 5.33 (2H, s), 3.70 (3H, s), 2.87 (2H, t), 2.78(2H, t), 1.98-2.06 (2H, m).

Step-II: Preparation of3-Dimethylamino-2-(7-Methoxy-indan-4-yloxy)-1-Thiophen-2-yl-propenone

The compound obtained in step-I of example-2 (2.0 gm, 0.0069 mole) wasadded into 5 ml N,N-dimethylformamide diethylacetal at room temperatureand stirred at 90° C. for 2 hours. The reaction mixture was poured intochilled water (100 ml) and extracted with Ethyl acetate. The Ethylacetate layer was washed with water, dried over Sodium sulphate andevaporated to give an oily product (1.9 gm). It was used for the nextstep.

Yield: 79.5%

Step-III: Preparation of4-(7-Methoxy-indan-4-yloxy)-3-thiophen-2-yl-1H-pyrazole and4-(7-Methoxy-indan-4-yloxy)-5-thiophen-2-yl-1H-pyrazole

To the clear solution of the compound obtained in step-II of example 2(1.9 gm, 0.0055 mole) in Ethanol (30 ml), Hydrazine hydrate (0.5 ml,0.0102 mole) was added and stirred at 60° C. for 4 hours. Ethanol wasevaporated under vacuum and water was added into the reaction mixture.It was extracted with Ethyl acetate (2×50 ml). The Ethyl acetate layerwas dried over Sodium sulphate and distilled under vacuum to give acrude product which was purified by column chromatography using Ethylacetate in Hexane (20:80) as mobile phase. The collected eluent wasevaporated under vacuum to yield 1.0 gm of the desired product.

Yield: 58.13%

¹H-NMR (400 MHz, DMSO-d₆):

For major isomer δ 12.82 (1H, s), 7.67 (1H, d), 7.43 (1H, d), 7.24 (1H,d), 7.02-7.08 (1H, m), 6.65 (1H, d), 6.56 (1H, d), 3.70 (3H, s), 2.92(2H, t), 2.82 (2H, t), 2.03-2.10 (2H, m).

Step-IV: Synthesis of3-[4-(7-Methoxy-indan-4-yloxy)-3-thiophen-2-yl-pyrazol-1-yl]-propionicacid ethyl ester and3-[4-(7-Methoxy-indan-4-yloxy)-5-thiophen-2-yl-pyrazol-1-yl]-propionicacid ethyl ester

It is prepared using the same method described for step-IV forexample-1.

Yield: 45.4%

¹H-NMR (400 MHz, DMSO-d₆): For major isomer δ 7.64 (1H, s), 7.45 (1H,dd), 7.26 (1H, dd), 703-7.07 (1H, m), 6.67 (1H, d), 6.62 (1H, d), 4.30(2H, t), 4.01-4.09 (2H, m), 3.72 (3H, s), 2.78-2.90 (6H, m), 2.04-2.07(2H, m), 1.13 (3H, t).

Step-V: Preparation of3-[4-(7-Methoxy-indan-4-yloxy)-3-thiophen-2-yl-pyrazol-1-yl]-propionicacid and3-[4-(7-Methoxy-indan-4-yloxy)-5-thiophen-2-yl-pyrazol-1-yl]-propionicacid

To a clear solution of the compound obtained in step-IV (0.6 gm, 0.0014mole) in Methanol (5.0 ml), A solution of Sodium hydroxide (0.12 gm,0.0029 mole) in water (25 ml) was added and stirred for 2 hours at roomtemperature. Methanol was distilled under vacuum completely the residualaqueous layer was washed with Ether (20 ml), acidified with diluteHydrochloric acid and extracted with Ethyl acetate (2×50 ml). Theseparated Ethyl acetate layer was dried over sodium sulphate anddistilled under vacuum to give acid derivative (440 mg) as a solid.

Yield: 78.7%

¹H-NMR (400 MHz, DMSO-d₆): for major isomer δ 12.42 (1H, bs), 7.64 (1H,s), 7.44 (1H, d), 7.26 (1H, d), 7.05 (1H, dd), 6.66 (1H, d), 6.62 (1H,d), 4.26 (2H, t), 3.72 (3H, s), 2.78-2.90 (6H, m), 2.01-2.06 (2H, m).

Step-VI: Preparation of3-[4-(7-Hydroxy-indan-4-yloxy)-3-thiophen-2-yl-pyrazol-1-yl]-propionicacid And3-[4-(7-Hydroxy-indan-4-yloxy)-5-thiophen-2-yl-pyrazol-1-yl]-propionicacid

To a clear solution of compound obtained in step-V of example-2 (0.44gm, 0.00118 mole) in Methylene chloride (20 ml), a solution of Borontribromide (0.35 ml, 0.0037 mole) in Methylene chloride (5 ml) was addedat 0-10° C. in drop wise manner and stirred for 2 hours at roomtemperature (25-28° C.). Water (10 ml) was slowly added to reactionmixture and extracted with Methylene chloride (2×30 ml). The separatedMethylene chloride layer was dried over Sodium sulphate and distilledunder vacuum to give desired product (200 mg) as a solid.

Yield: 47.1%

¹H-NMR (400 MHz, DMSO-d₆):

For major isomer δ 12.41 (1H, s), 9.00 (1H, s), 7.55 (1H, s), 7.44 (1H,d), 7.29 (1H, d), 7.04-7.06 (1H, m), 6.46-6.54 (2H, m), 4.24 (2H, t),2.73-2.84 (6H, m), 1.96-2.06 (2H, m).

MASS: 369 (M⁺−1)

Example-3 Compound No. 37-[3,5-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-1H-pyrazol-4-yloxy]-indan-4-olStep-I: Preparation of[4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile

It was prepared by using similar method as described for step-IV ofexample-1 using Bromoacetonitrile instead of Ethyl 3-chloropropionate.

Yield: 96.7%

¹H-NMR (400 MHz, DMSO-d₆): δ 6.63 (1H, d), 6.31 (1H, d), 5.35 (2H, s),3.70 (3H, s), 2.89 (2H, t), 2.80 (2H, t), 2.10 (3H, s), 1.98-2.07 (2H,m), 1.93 (3H, s).

Step-II: Preparation of5-[4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-ylmethyl]-1H-tetrazole

To a stirred solution of[4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile(3.0 gm, 0.0101 mole) in Dimethylformamide (30 ml), Sodium azide (1.2gm, 0.0185 mole) and Triethylamine hydrochloride (4.0 gm, 0.0303 mole)were added at room temperature (27-30° C.). The reaction mixture wasstirred at 90-100° C. for 4 hours. The reaction mixture was cooled andpoured into dilute Hydrochloric acid (100 ml) and stirred for 30minutes. The separated solid was filtered and dissolved in Ethyl acetate(100 ml). The Ethyl acetate layer was dried over Sodium sulphate anddistilled under vacuum to get a 1.5 gm of desired product as a solid.

Yield: 43.7%

¹H-NMR (400 MHz, DMSO-d₆): δ 6.62 (1H, d), 6.32 (1H, d), 5.57 (2H, s),3.70 (3H, s), 2.89 (2H, t), 2.80 (2H, t), 2.11 (3H, s), 2.03-2.09 (2H,m), 1.89 (3H, s).

Step-III:7-[3,5-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-1H-pyrazol-4-yloxy]-indan-4-ol

It was prepared by using similar method as described for step-VI ofexample-2.

Yield: 31.3%

¹H-NMR (400 MHz, DMSO-d₆): δ 8.85 (1H, s), 6.44 (1H, d), 6.21 (1H, d),5.55 (2H, s), 2.84 (2H, t), 2.76 (2H, t), 2.11 (3H, s), 2.00-2.06 (2H,m), 1.88 (3H, s).

Mass: 325 (M⁺−1)

Example-4 Compound No. 105-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-ylmethyl]-1H-pyrazol-3-olStep-I: Preparation of4-[4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-3-oxo-butyricacid ethyl ester

It was prepared by using similar method as described for step-IV ofexample-1 using 4-Chloro-3-oxo-butyric acid ethyl ester as an alkylatingagent instead of Ethyl 3-chloropropionate.

Yield: 35.7%

¹H-NMR (400 MHz, DMSO-d₆): δ 6.64 (1H, d), 6.33 (1H, d), 5.11 (2H, s),4.11 (2H, q), 3.69-3.70 (5H, m), 2.87-2.92 (2H, m), 2.80 (2H, t),2.02-2.07 (2H, m), 1.92 (3H, s), 1.90 (3H, s), 1.19 (3H, t).

Step-II: Preparation of5-[4-(7-Methoxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-ylmethyl]-1H-pyrazol-3-ol

To a stirred solution of keto ester of step-I of example-4 (0.8 gm,0.00207 mole) in Methanol (20 ml), a solution of Hydrazine hydrate (0.11ml, 0.00227 mole) in Methanol (5 ml) was added at 0-10° C. The reactionmixture was heated to 75-80° C. and stirred for 12 hours. The Methanolwas distilled under vacuum and obtained solid was stirred in Ethylacetate (5 ml). Further it was filtered, suck dried to give 380 mg ofdesired product as a solid.

Yield: 51.8%

¹H-NMR (400 MHz, DMSO-d₆): δ 11.81 (1H, bs), 9.57 (1H, bs), 6.61 (1H,d), 6.28 (1H, d), 5.27 (1H, bs), 5.03 (2H, bs), 3.69 (3H, s), 2.88 (2H,t), 2.80 (2H, t), 2.01-2.08 (5H, m), 1.90 (3H, s).

Step-III: Preparation of5-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-ylmethyl]-1H-pyrazol-3-ol

It was prepared by using similar method as described for step-VI ofexample-2.

Yield: 60.4%

¹H-NMR (400 MHz, DMSO-d₆): δ 8.82 (1H, bs), 6.41 (1H, d), 6.15 (1H, d),5.22 (1H, s), 5.01 (2H, s), 2.82 (2H, t), 2.74 (2H, t), 1.93-2.06 (5H,m), 1.84 (3H, s).

Mass: 339 (M⁺−1)

Example-5 Compound No. 19[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid Step-I: Preparation of 7-Chloromethyl-4-methoxy-5-methyl-indan

To a stirred solution of 7-Methoxy-6-methyl-indan-4-carboxaldehyde (39gm, 0.205 mole)

In Methanol (200 ml), Sodium borohydride (9.5 gm, 0.225 mole) was addedin portions at 10-20° C. and stirred at room temperature for 2 hours.The reaction mixture was poured into water (200 ml) and acidified withdilute Hydrochloric acid to pH 6. The reaction mixture was subjected todistillation under vacuum and then extracted with Ethyl acetate (2×200ml). The Ethyl acetate layer was dried over Sodium sulphate anddistilled under vacuum to give 38 gm viscous oil. To a clear solution ofviscous oil (38.0 gm) in Methylene chloride (160 ml), Thionyl chloride(29.07 ml, 0.396 mole) was added at 10-15° C. and stirred at 20-25° C.for 2 hrs. The reaction mixture was poured into the water (200 ml). Theseparated organic layer was washed with saturated Sodium bicarbonate,dried over Sodium sulphate, distilled under vacuum to yield crudeproduct as a solid. The crude solid was dissolved in Hexane, filteredand then the filtrate was distilled off to give a desired compound (36.0gm) as solid.

Yield: 83.5%

¹H-NMR (400 MHz, DMSO-d₆): δ 6.95 (1H, s), 4.66 (2H, s), 3.70 (3H, s),2.85-2.98 (4H, m), 2.15 (3H, s), 1.99-2.05 (2H, m).

Step-II: Preparation of3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-1H-pyrazole

To a stirred suspension of 3,5-Heptanedione (8.7 ml, 0.0642 mole) andPotassium carbonate (15.0 gm, 0.1086 mole) in Dimethylformamide (50 ml),the solution of 7-Chloromethyl-4-methoxy-5-methyl-indan (15.0 gm, 0.0714mole) in Dimethylformamide (25 ml) was added slowly and stirred for2.5-3 hrs at 40-45° C. To the reaction mixture, water (500 ml) was addedthen acidified with dilute Hydrochloric acid and extracted with Ethylacetate (2×500 ml). The Ethyl acetate layer was dried over Sodiumsulphate and distilled under vacuum to give 20 gm of diketo derivativeas viscous oil. To a clear solution of obtained viscous oil in Isopropylalcohol (80 ml), a solution of 99% Hydrazine hydrate (3.3 ml, 0.066mole) in Isopropyl alcohol (20 ml) was added slowly at 15-20° C. Thereaction mixture was heated to 80-85° C. and stirred for 1 hour. TheAcetic acid (7.5 ml) was added and heating was continued for another11-12 hrs. The Isopropyl alcohol was distilled and residue was portionedbetween aqueous Sodium bicarbonate (200 ml) and Ethyl acetate (2×200ml). The Ethyl acetate layer was dried over Sodium sulphate anddistilled under vacuum to give a solid. The obtained solid was stirredin Hexane (50 ml), filtered and dried under vacuum to give 9.3 gm ofdesired Pyrazole.

Yield: 43.7%

¹H-NMR (400 MHz, DMSO-d₆): 12.02 (1H, s), 6.46 (1H, s), 3.64 (3H, s),3.51 (2H, s), 2.84-2.88 (2H, m), 2.75 (2H, t), 2.36-2.40 (4H, m), 2.06(3H, s), 1.96-2.04 (2H, m), 1.00-1.04 (6H, m).

Step-III: Preparation of[3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid ethyl ester

To a stirred solution of Pyrazole derivative obtained in step-II ofexample-5 (9.0 gm, 0.0302 mole) and Ethyl bromo acetate (6.7 ml, 0.0604mole) in Dimethylformamide (50 ml), Cesium carbonate (14.7 gm, 0.0453mole) was added and stirred for 16 hour at room temperature (25-30° C.).The reaction mixture was poured into water (400 ml). The separated solidwas filtered and washed well with water (50 ml) and suck dried. Thesolid cake was dissolved in Ethyl acetate (200 ml) and washed withwater. The Ethyl acetate layer was dried over Sodium sulphate anddistilled under vacuum to get crude solid. The crude solid was stirredin Hexane (50 ml) for 2 hour, filtered, washed with Hexane (10 ml) anddried under vacuum to get desired product as off white solid (9.0 gm)

Yield: 77.6%

¹H-NMR (400 MHz, DMSO-d₆): δ 6.47 (1H, s), 4.90 (2H, s), 4.12 (2H, q),3.64 (3H, s), 3.54 (2H, s), 2.85-2.89 (2H, m), 2.73-2.77 (2H, m), 2.44(2H, q), 2.30 (2H, q), 2.06 (3H, s), 1.96-2.04 (2H, m), 1.19 (3H, t),1.00 (3H, t), 0.89 (3H, t).

Step-IV: Preparation of[3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid

To a stirred solution of[3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid ethyl ester of step-III (9.0 gm, 0.0234 mole) in Tetrahydrofuran(40 ml) and Methanol (20 ml), a solution of Sodium hydroxide (1.87 gm,0.0468 mole) in water (75 ml) was added at 20-30° C. and stirred for1.5-2 hours. The reaction mixture was poured into water (50 ml) andextracted with Ethyl acetate (2×200 ml). The residual aqueous layer wasacidified with dilute Hydrochloric acid. The separated solid wasfiltered, washed well with water (50 ml) and dried under vacuum at60-65° C. to yield desired product as off white solid. (6.3 gm).

Yield: 75.5%

¹H-NMR (400 MHz, DMSO-d₆): δ 12.80-13.00 (1H, bs), 6.48 (1H, s), 4.79(2H, s), 3.64 (3H, s), 3.54 (2H, s), 2.85-2.89 (2H, m), 2.74-2.78 (2H,m), 2.44 (2H, q), 2.30 (2H, q), 2.06 (3H, s), 1.96-2.04 (2H, m), 1.00(3H, t), 0.90 (3H, t).

Step-V: preparation of[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid

To a stirred suspension of[3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid (6.0 gm, 0.0168 mole) in Methylene chloride (100 ml), a solution ofBoron tribromide (4.2 ml, 0.0442 mole) in Methylene chloride (20 ml) wasadded at 0-5° C. and stirred for 2-3 hrs at 20-30° C. Water (250 ml) wascharged into the reaction mixture and stirred for 1 hour. The separatedsolid was filtered under vacuum, washed with water. The obtained solidwas dissolved in Ethyl acetate (2.0 liter) and washed with water (1liter). Ethyl acetate was distilled under vacuum and further theobtained solid was stirred in Diethyl ether (50 ml), filtered and driedat 55-60° C. under vacuum to yield 4.5 gm of desired product.

Yield: 78.3%

¹H-NMR (400 MHz, DMSO-d₆): δ 8.14 (1H, s), 6.39 (1H, s), 4.77 (2H, s),3.48 (2H, merged with peak of water present in DMSO-d6), 2.68-2.77 (4H,m), 2.43 (2H, q), 2.30 (2H, q), 1.94-2.01 (5H, m), 1.00 (3H, t), 0.90(3H, t).

¹H-NMR (400 MHz, CD₃OD): δ 6.66 (1H, s), 4.83 (2H, s), 3.59 (2H, s),2.75-2.83 (4H, m), 2.51 (2H, q), 2.42 (2H, q), 1.91-2.07 (5H, m), 1.05(3H, t), 0.97 (3H, t).

Mass: 341 (M⁺−1)

Example-6 Compound No. 333-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-N-isopropyl-propionamideStep-I Preparation of3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionicacid

It was prepared by using similar method as described for step-IV ofexample-5

Yield: 54.0%

¹H-NMR (400 MHz, DMSO-d₆): δ 12.29 (1H, bs), 6.49 (1H, s), 4.10 (2H, t),3.64 (3H, s), 3.48 (2H, s), 2.86 (2H, t), 2.68-2.75 (4H, m), 2.10 (3H,s), 2.08 (3H, s), 1.96-2.03 (2H, m), 1.92 (3H, s).

Step-II: Preparation ofN-Isopropyl-3-[4-(7-methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionamide

To the solution of3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionicacid (1.0 gm, 0.00292 mole) in Tetrahydrofuran (20 ml),Carbonyl-diimidazole (0.62 gm, 0.0038 mole) was added at 20-30° C. Thereaction mixture was heated and stirred for an hour at 70-75° C. Asolution of Isopropyl amine (0.3 ml, 0.00367 mole) in Tetrahydrofuran (5ml) was added at 20-30° C. The reaction mixture was further stirred at70° C. for 4 hours. The reaction mixture was cooled and poured intowater (50 ml) and extracted with Ethyl acetate (2×100 ml). The Ethylacetate layer was dried over Sodium sulphate, distilled under vacuum toget a crude product which was stirred in Hexane (20 ml) and filtered togive 810 mg of desired product as a solid.

Yield: 72.8%

¹H-NMR (400 MHz, DMSO-d₆): δ 7.77 (1H, d), 6.49 (1H, s), 4.10 (2H, t),3.77 (1H, m), 3.64 (3H, s), 3.47 (2H, s), 2.86 (2H, t), 2.73 (2H, t),2.49 (2H, merged with DMSO-d6 peak), 2.08 (6H, s), 1.95-2.03 (2H, m),1.92 (3H, s), 0.98 (6H, d).

Step-III: Preparation of3-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-N-isopropylpropionamide

It was prepared by using similar method as described for step-VI ofexample-2

Yield: 51.9%

¹H-NMR (400 MHz, DMSO-d₆):

δ 8.11 (1H, s), 7.76 (1H, d), 6.40 (1H, s), 4.08 (2H, t), 3.76-3.81 (1H,m), 3.42 (2H, s), 2.75 (2H, t), 2.69 (2H, t), 2.51 (2H, merged withDMSO-d6 peak), 2.07 (3H, s), 2.02 (3H, s), 1.90-1.99 (5H, m), 0.98 (6H,d).

Mass: 370 (M⁺+1)

Example-7 Compound No. 425-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-ylmethyl]-3H-[1,3,4]oxadiazol-2-oneStep-I: Preparation of[3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid hydrazide

A stirred suspension of[3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid ethyl ester (3.3 gm, 0.0085 mole) and 99% Hydrazine hydrate (33 ml)was heated at 60-65° C. for 3 hours. The reaction mixture was pouredinto water (200 ml), stirred for an hour and then filtered. The obtainedsolid was stirred in Methanol (10 ml), filtered and dried to give 2.9 gmof desired product as a solid.

Yield: 91.4%

¹H-NMR (400 MHz, DMSO-d₆): δ 9.23 (1H, s), 6.51 (1H, s), 4.58 (2H, s),4.29-4.30 (2H, d), 3.64 (3H, s), 3.52 (2H, s), 2.87 (2H, t), 2.76 (2H,t), 2.47 (2H, merged with DMSO-d6 peak), 2.30 (2H, q), 2.07 (3H, s),1.97-2.04 (2H, m), 1.00 (3H, t), 0.90 (3H, t).

Step-II: Preparation of5-[3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-ylmethyl]-3H-[1,3,4]oxadiazol-2-one

To a stirred solution of[3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-aceticacid hydrazide (1.5 gm, 0.0041 mole) in 1,4-Dioxane (70 ml),Carbonyl-diimidazole (2.0 gm, 0.0121 mole) was added at 20-30° C. Thereaction mixture was stirred for 8 hours at 90-95° C. The reactionmixture was cooled and poured into water (200 ml), stirred for 2 hoursand then separated solid was filtered. Further the solid was stirred inDiethyl ether (25 ml) and filtered, dried to give 900 mg of desiredproduct as a solid.

Yield: 56.2%

¹H-NMR (400 MHz, DMSO-d₆): δ 12.28 (1H, bs), 6.45 (1H, s), 5.20 (2H, s),3.64 (3H, s), 3.54 (2H, s), 2.87 (2H, t), 2.74 (2H, t), 2.54 (2H, q),2.31 (2H, q), 2.06 (3H, s), 1.98-2.01 (2H, m), 1.00 (3H, t), 0.92 (3H,t).

Step-III: Preparation of5-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-ylmethyl]-3H-[1,3,4]oxadiazol-2-one

It was prepared by using similar method as described for step-VI ofexample-2.

Yield: 70.7%

¹H-NMR (400 MHz, DMSO-d₆): δ 12.41 (1H, s), 8.14 (1H, s), 6.37 (1H, s),5.20 (2H, s), 3.49 (2H, s), 2.69-2.77 (4H, m), 2.53 (2H, merged withDMSO-d6 peak), 2.31 (2H, q), 1.91-2.01 (5H, m), 0.99 (3H, t), 0.92 (3H,t).

Mass: 383 (M⁺+1)

Example-8 Compound No. 456-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-ylmethyl]-2-methyl-3H-pyrimidin-4-oneStep-I: Preparation of4-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-3-oxo-butyricacid ethyl ester

It was prepared by using similar method as described for step-IV ofexample-1 using 4-Chloro-3-oxo-butyric acid ethyl ester as an alkylatingagent instead of Ethyl 3-chloropropionate.

Yield: 47.1%

¹H-NMR (400 MHz, DMSO-d₆): 6.53 (1H, s), 5.07 (2H, s), 4.4.08 (2H, q),3.64 (3H, s), 3.63 (2H, s), 3.51 (2H, s), 2.86 (2H, t), 2.74 (2H, t),2.09 (3H, s), 1.97-2.05 (5H, m), 1.92 (3H, s), 1.18 (3H, t)

Step-II: Preparation of6-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-ylmethyl]-2-methyl-3H-pyrimidin-4-one

To the solution of4-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-3-oxo-butyricacid ethyl ester (1.0 gm, 0.0025 mole) in Ethanol (60 ml), Acetamidinehydrochloride (0.71 gm, 0.0075 mole) was added. Further to this, Sodiumethoxide (0.51 gm, 0.0075 mole) was added at 5-10° C. and then stirredat 70-75° C. for 2 hours. The Ethanol was distilled under vacuum andresidue was partitioned between Ethyl acetate (100 ml) and water (100ml). Further aqueous layer was extracted with Ethyl acetate (2×100 ml).The combined volume of Ethyl acetate layer was reduced to 20 ml and thenfiltered to give 800 mg of desired product.

Yield: 81.3%

¹H-NMR (400 MHz, DMSO-d₆): δ 12.42 (1H, bs), 6.50 (1H, s), 5.16 (1H, s),4.97 (2H, s), 3.64 (3H, s), 3.55 (2H, s), 2.87 (2H, t), 2.74 (2H, t),2.27 (3H, s), 2.09 (3H, s), 2.05 (3H, s), 1.98-2.02 (2H, m), 1.95 (3H,s).

Step-III: Preparation of6-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-ylmethyl]-2-methyl-3H-pyrimidin-4-one

It was prepared by using similar method as described for step-VI ofexample-2

Yield: 58.4%

¹H-NMR (400 MHz, DMSO-d₆): δ 12.41 (1H, s), 8.12 (1H, s), 6.42 (1H, s),5.13 (1H, s), 4.95 (2H, s), 3.49 (2H, s), 2.67-2.77 (4H, m), 2.26 (3H,s), 2.03 (6H, s), 1.94-1.99 (5H, m).

Mass: 379 (M⁺+1)

Example-9 Compound No. 463-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-ylmethyl]-[1,2,4]oxadiazol-5-olStep-I: Preparation of[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile

It was prepared by using similar method as described for step-IV ofexample-1 using Bromoacetonitrile as an N-alkylating agent instead ofEthyl 3-chloropropionate.

Yield: 52.8%

¹H-NMR (400 MHz, DMSO-d₆): δ 6.51 (1H, s), 5.31 (2H, s), 3.64 (3H, s),3.52 (2H, s), 2.87 (2H, t), 2.73 (2H, t), 2.15 (3H, s), 2.09 (3H, s),1.92-2.03 (5H, m).

Step-II: Preparation ofN-Hydroxy-2-[4-(7-methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-acetamidine

To a stirred solution of[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile(2.0 gm 0.00647 mole) in methanol (50 ml), A suspension of Hydroxylaminehydrochloride (2.29 gm, 0.033 mole) and Potassium carbonate (4.37 gm,0.0317 mole) in water (20 ml) was added. The reaction mixture wasstirred for 30-36 hours at 70° C., cooled and then was filtered. Theobtained solid was washed with water (10 ml) and finally with Hexane anddried under vacuum to give 1.8 gm of desired product

Yield: 81.4%

¹H-NMR (400 MHz, DMSO-d₆): δ 9.20 (1H, bs), 6.52 (1H, s), 5.24 (2H, s),4.51 (2H, s), 3.64 (3H, s), 3.49 (2H, s), 2.86 (2H, t), 2.74 (2H, t),2.09 (6H, s), 1.98-2.05 (2H, m), 1.94 (3H, s).

Step-III: Preparation of3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-ylmethyl]-[1,2,4]oxadiazol-5-ol

To the solution ofN-Hydroxy-2-[4-(7-methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-acetamidine(2.4 gm, 0.00701 mole) in Pyridine (50 ml), Ethyl chloroformate (1.5 ml,0.0157 mole) was added at 0-5° C. The reaction mixture was stirred for15 minutes and Pyridine was distilled under vacuum. To the obtainedresidue, the mixture of water and Tetrahydrofuran (1:1) 40 ml and 1MSodium hydroxide solution (10 ml) were added and stirred at 75° C. foran hour and continued for 24 hours at 25-28° C. To the reaction mixture,2M Hydrochloric acid (200 ml) was added and extracted with Ethyl acetate(2×100 ml). Ethyl acetate layer was dried over sodium sulphate anddistilled under vacuum to give a 2.0 gm solid. The obtained solid wastaken in mixture of Tetrahydrofuran (5 ml) and 1M Sodium hydroxide (50ml) and refluxed for 24 hours. The reaction mixture was cooled and 2Nhydrochloric acid (100 ml) was added. The separated solid was filtered,washed with water (20 ml) and dissolved in Ethylacetate (100 ml). TheEthyl acetate layer was dried over Sodium sulphate and distilled undervacuum to give 880 mg of desired product as a solid

Yield: 34.10%

¹H-NMR (400 MHz, DMSO-d₆): δ 6.52 (1H, s), 5.14 (2H, s), 3.64 (3H, s),3.51 (2H, s), 2.86 (2H, t), 2.74 (2H, t), 2.13 (3H, s), 2.08 (3H, s),1.95-2.03 (2H, m), 1.94 (3H, s).

Step-IV: Preparation of3-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-ylmethyl]-[1,2,4]oxadiazol-5-ol

It was prepared by using similar method as described for step-VI ofexample-2

Yield: 79.5%

¹H-NMR (400 MHz, DMSO-d₆): δ 8.15 (1H, s), 6.44 (1H, s), 5.14 (2H, s),3.46 (2H, s), 2.68-2.77 (4H, m), 2.13 (3H, s), 2.03 (3H, s), 1.87-1.99(5H, m).

Mass: 353 (M⁺−1)

Example-10 Compound No. 66 Propane-2-sulfonic acid{3-[4-(7-methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionyl}-amide

To the suspension of 60% Sodium hydride (76 mg, 0.0019 mole) inTetrahydrofuran (2 ml), the solution of3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionamide(500 mg, 0.00146 mole) in Tetrahydrofuran (5 ml) was added at roomtemperature and stirred for 20 minutes. A solution of Isopropyl sulfonylchloride (0.18 ml, 0.0016 moles) in Tetrahydrofuran (3 ml) was added at0-5° C. and stirred at 15-25° C. for 3 hours. Tetrahydrofuran wasdistilled under vacuum, dilute hydrochloric acid (20 ml) was added tothe reaction mixture and extracted with Ethyl Acetate (50 ml). The Ethylacetate layer was dried over Sodium sulphate and distilled under vacuumto give a crude product which was purified by column chromatographyusing Ethylacetate as a mobile phase. The fractions were distilled togive 80 mg of desired compound as a solid.

Yield: 12.2%

¹H-NMR (400 MHz, DMSO-d₆): δ 11.50 (1H, bs), 6.49 (1H, s), 4.12 (2H, t),3.64 (3H, s), 3.51-3.55 (1H, m), 3.47 (2H, s), 2.80-2.88 (4H, m), 2.73(2H, t), 2.09 (3H, s), 2.08 (3H, s), 1.96-2.03 (2H, m), 1.91 (3H, s),1.20 (6H, d).

Mass: 446 (M⁺−1)

Example-11 Compound No. 127-[1-(2-Hydroxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-methyl-indan-4-olStep-I: Preparation of3-(7-Methoxy-6-methyl-indan-4-ylmethyl)-pentane-2,4-dione

To the solution of 7-Methoxy-6-methyl-indan-4-carbaldehyde (8.0 gm 0.042mole) and Acetyl acetone (4.63 gm, 0.046 mole) in Toluene (80 ml),Piperidine (0.5 ml) and Acetic acid (0.5 ml) were added. The reactionmixture was refluxed over 3 A° molecular sieve using dean starkapparatus for 24 hours. Toluene was distilled under vacuum to give acrude product, which was purified by column chromatography using 5%Ethyl acetate in Hexane. The fractions were distilled to give 3.0 gm ofcondensed product It was dissolved in Methanol (60 ml) and hydrogenationwas carried out over 5% w/w Palladium on Barium sulphate (350 mg) at40-50 psi. using Hydrogen gas at 25-30° C. The reaction mixture wasfiltered through hyflow bed and distilled under vacuum to give a 2.9 gmof desired compound as a viscous oil.

Yield: 25.1%

Mass: 274 (M⁺−1)

Step-II: Preparation of2-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-ethanol

To a stirred solution of3-(7-Methoxy-6-methyl-indan-4-ylmethyl)-pentane-2,4-dione (1.0 gm 0.0036mole) in Ethanol (15 ml), a solution of 2-Hydrazino-ethanol (0.33 gm,0.0043 mole) in Ethanol (5 ml) was added at 25-30° C. and reactionmixture was heated to 70° C. for an hour. The Acetic acid (2 ml) wasadded. Further the reaction mixture was stirred at 70° C. for 3 hours.Ethanol was distilled under vacuum to give a residue which waspartitioned between Ethyl acetate (50 ml) and water (25 ml). Ethylacetate was distilled under vacuum to give a crude product The crudeproduct was solidified after stirring in Diethyl ether (10 ml). Thesolid was filtered under vacuum and dried to give a 700 mg of desiredcompound as a solid.

Yield: 61.4%

Mass: 315 (M⁺+1)

Step-III: Preparation of7-[1-(2-Hydroxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-methyl-indan-4-ol

It was prepared by using similar method as described for step-VI ofexample-2

Yield: 45.4%

¹H-NMR (400 MHz, DMSO-d₆): δ 8.11 (1H, s), 6.43 (1H, s), 4.80 (1H, t),3.95 (2H, t), 3.63 (2H, q), 3.43 (2H, s), 2.69-2.77 (4H, m), 2.08 (3H,s), 2.03 (3H, s), 1.92-1.99 (5H, m).

Mass: 301 (M⁺+1)

Following is the Process for the Preparation of Intermediates, whichwere Used for the Preparation of Compounds Mentioned in Table-1:

Preparation of Intermediates 1: Preparation of7-Methoxy-6-methyl-indan-4-carbaldehyde Method-1 Step-I: Preparation of8-Methyl coumarin

The suspension of 2-Hydroxy-3-methyl benzaldehyde (30 gm, 0.220 mole)and anhydrous Sodium acetate (45 gm, 0.55 mole) in Acetic anhydride (45gm, 0.44 mole) was heated at 175-180° C. for 6 hours. The reactionmixture was cooled; water (150 ml) and Hexane (60 ml) were added. It wasstirred for an hour and filtered. The obtained solid was stirred withDiethyl ether (30 ml). Finally the suspension was filtered and dried togive 19 gm desired product.

Yield: 85%

NMR (400 mhz, CDCl₃): δ 7.69 (1H, d), 7.35-7.37 (1H, m), 7.30-7.32 (1H,m), 7.16 (1H, t), 6.39 (1H, d), 2.44 (3H, s).

Step-II: Preparation of 8-Methyl dihydrocoumarin

To a solution of 8-Methyl coumarin (16.2 gm) in Ethyl acetate (160 ml),10% w/w Palladium-charcoal (1.62 gm) was added. Hydrogenation wascarried out for 5 hours at 55-60° C. in an autoclave at 240-250 psi.using Hydrogen gas. The reaction mixture was filtered through hyflow bedand distilled under vacuum to give a 14.5 gm of title compound as awhite solid.

Yield: 90%

NMR (400 mhz, DMSO-d₆): δ 7.10-7.14 (2H, m), 7.01 (1H, t), 2.93-2.97(2H, m), 2.73-2.76 (2H, m), 2.21 (3H, s).

Step-III: Preparation of 4-Hydroxy-5-methyl-indan-1-one

The mixture of 8-Methyl dihydrocoumarin (20 gm, 0.123 mole) and Aluminumtrichloride (49.3 gm, 0.370 mole) was stirred for 2 hours at 175-180° C.To the reaction mixture, water (250 ml) was added slowly and stirred foran hour. Further it was filtered and obtained solid was stirred inMethanol (60 ml). Finally the suspension was filtered and obtained solidwas dried under vacuum to give 13.5 gm of desired product as a solid.

Yield: 67.5%

NMR (400 mhz, DMSO-d₆): δ 9.22 (1H, s), 7.15 (1H, d), 7.04 (1H, d), 2.96(2H, t), 2.59 (2H, t), 2.24 (3H, s)

Step-IV: Preparation of 5-Methyl-indan-4-ol

To a suspension of 4-Hydroxy-5-methyl-indan-1-one (8 gm) in Methanol (80ml), added 10% w/w Pd—C. Hydrogenation was carried out for 5 hours at55-60° C. in an autoclave at 200-250 psi using Hydrogen gas. Thereaction mixture was filtered through hyflow bed and filtrate wasdistilled under vacuum to give a 6.0 gm of desired product as whitesolid.

Yield: 82.2%

NMR (400 mhz, DMSO-d₆): δ 8.36 (1H, s), 6.82 (1H, d), 6.58 (1H, d),2.73-2.79 (4H, m), 2.10 (3H, s), 1.92-1.99 (2H, m)

Step-V: Preparation of 7-Hydroxy-6-methyl-indan-4-carbaldehyde

To a clear solution of 5-Methyl-indan-4-ol (6 gm, 0.0405 mole) in 30 mlTrifluoroacetic acid, Hexamine (5.7 gm, 0.0405 mole) was added at 25-28°C. The reaction mixture was heated and stirred at 85-90° C. for 6 hours.The cooled reaction mixture was poured into saturated Sodium bicarbonatesolution and extracted with Ethylacetate (2×200 ml). The organic layerwas dried over Sodium sulphate and distilled under vacuum to give acrude product which was purified by column chromatography using Ethylacetate:Hexane (10:90) as mobile phase The collected fractions weredistilled to give 5.4 gm of desired product as a solid.

Yield: 76%

NMR (400 mhz, DMSO-d₆): δ 9.87 (1H, s), 9.63 (1H, bs), 7.44 (1H, s),3.14 (2H, t), 2.79 (2H, t), 2.18 (3H, s), 1.99-2.08 (2H, m).

Step-VI: Preparation of 7-Methoxy-6-methyl-indan-4-carbaldehyde

To a stirred suspension of 6-Methyl-7-hydroxy-indan-4-carbaldehyde (5gm, 0.0284 mole) and Potassium carbonate (4.7 gm, 0.0340 mole) indimethyl formamide, Methyl iodide (2.2 ml, 0.0312 mole) was added at 0°C. The reaction mixture was stirred at 25-30° C. for 4 hours, then water(200 ml) was added and extracted with Ethylacetate (2×100 ml). TheEthylacetate layer was dried over Sodium sulphate and evaporated to givea crude mass which was purified by column chromatography using Ethylacetate:Hexane (10:90) as a mobile phase. The fractions were distilledunder vacuum to give 4.8 gm of desired product as viscous oil.

Yield: 88.9%

NMR (400 mhz, DMSO-d₆): δ 9.97 (1H, s), 7.50 (1H, s), 3.84 (3H, s), 3.14(2H, t), 2.96 (2H, t), 2.22 (3H, s), 2.01-2.08 (2H, m)

MASS: 191 (M⁺+1)

Method-2 Step-I: Preparation of 4-Hydroxy-indan-5-carbaldehyde

To a stirred suspension Magnesium chloride (71.0 gm, 0.745 mole) andPara-formaldehyde (33.6 gm, 1.12 mole) in Tetrahydrofuran (200 ml),Triethylamine (104 ml, 0.745 mole) was added at room temperature andstirred for 30 minutes. To the reaction mixture; the solution ofIndan-4-ol (50 gm, 0.373) in Tetrahydrofuran (100 ml) was added at roomtemperature and heated to 70-75° C. for 6 hours. To the reactionmixture, 2N Hydrochloric acid (600 ml) was added and extracted withEthylacetate (2×500 ml). The Ethylacetate layer was washed with water(300 ml), dried over Sodium sulphate and further it was distilled undervacuum to give viscous oil (52.0 gm) which becomes solid upon keeping.

Yield: 86.0%

NMR (400 mhz, DMSO-d₆): δ 10.76 (1H, s), 10.04 (1H, s), 7.55 (1H, d),6.95 (1H, d), 2.91 (2H, t), 2.83 (2H, t), 2.02-2.09 (2H, m)

Step-II: Preparation of 5-Methyl-indan-4-ol

To a solution of 4-Hydroxy-indan-5-carbaldehyde (5 gm) in Methanol (80ml), 10% wt/wt Palladium-charcoal (500 mg) was added. The hydrogenationwas carried out for 8 hours at 55-60° C. in an autoclave at 240-250 psiusing Hydrogen gas. The reaction mixture was filtered through hyflow bedand distilled under vacuum to give 4.0 gm of title compound as a solid.

Yield: 88.0%

Step-III: Preparation of 7-Hydroxy-6-methyl-indan-4-carbaldehyde

It is prepared using procedure same as described for step-V of method-1for preparation of intermediate 1.

Step-IV: Preparation of 7-Methoxy-6-methyl-indan-4-carbaldehyde

It is prepared using procedure same as described for step-V of method-1for preparation of intermediate 1.

2: Preparation of 7-Methoxy-6-(4-methyl-benzyl)-indan-4-carbaldehydeStep-I: Preparation of 4-Methoxy-indan-5-carbaldehyde

To a stirred suspension of 4-Hydroxy-indan-5-carbaldehyde (52.0 gm,0.320 mole) and Potassium carbonate (57.2 gm, 0.414 mole) inDimethylformamide (200 ml) solution of Methyl iodide (22 ml, 0.351 mole)in 60 ml Dimethylformamide was added at 0-5° C. The reaction mixture wasstirred at 25-28° C. for 4 hours and then poured into water (200 ml),further it was extracted with Ethyl acetate (2×500 ml). The organiclayer was dried over Sodium sulphate, distilled under vacuum to givecrude product which was purified through column chromatography usingEthyl acetate:Hexane (3:97) as mobile phase. The collected fractionswere distilled under vacuum to give 30 gm of desired product as aviscous oil.

Yield: 53.0%

NMR (400 mhz, DMSO-d₆): δ 10.26 (1H, s), 7.54 (1H, d), 7.12 (1H, d),3.92 (3H, s), 3.01 (2H, t), 2.91 (2H, t), 2.03-2.10 (2H, m).

Step-II: Preparation of 4-Methoxy-5-(4-methyl-benzyl)-indan

To a stirred suspension of Magnesium turning (1.36 gm, 0.056 mole) in 60ml Diethyl ether, added 4-Bromo toluene (8.7 ml, 0.071 mole) in 20 mlDiethyl ether at 30-40° C. under nitrogen atmosphere. Further It wasstirred at 30-40° C. for 45 minutes. The solution of4-Methoxy-indan-5-carbaldehyde (5.0 gm, 0.0284 mole) in 20 ml Diethylether was added to the reaction mixture at room temperature. After anhour room temperature stirring, dilute Hydrochloric acid was added andextracted with Ethylacetate (2×100 ml). The organic layer was dried overSodium sulphate, distilled under vacuum to give 8.0 gm crude alcoholwhich was taken with Triethyl silane (40.0 ml, 0.250 mole) and addedTrifluoroacetic acid (80 ml) at 0-5° C. After stirring at 70° C. for 5hours, reaction mixture was poured into saturated Sodium bicarbonatesolution and extracted with Ethyl acetate (2×100 ml). The Ethyl acetatelayer was dried over Sodium sulphate and distilled to give a crude masswhich was purified by column chromatography using Ethyl acetate:Hexane(3:97) as a mobile phase. The fractions were distilled to give 5.6 gm ofpure product as viscous oil.

Yield: 78.2%

NMR (400 mhz, DMSO-d₆): δ 7.05-7.07 (4H, s), 6.90 (1H, d), 6.87 (1H, d),3.82 (2H, s), 3.62 (3H, s), 2.88 (2H, t), 2.79 (2H, t), 2.23 (3H, s),1.95-2.01 (2H, m).

Step-III: Preparation of7-Methoxy-6-(4-methyl-benzyl)indan-4-carbaldehyde

It is prepared using procedure same as described for step-V of method-1for preparation of intermediate 1.

Yield: 21%

NMR (400 mhz, DMSO-d₆): δ 9.97 (1H, s), 7.49 (1H, s), 7.07 (4H, s), 3.89(2H, s), 3.78 (3H, s), 3.16 (2H, t), 2.97 (2H, t), 2.24 (3H, s),2.02-2.09 (2H, m).

MASS: 281 (M⁺+1)

3. Preparation of 7-Methoxy-3,6-dimethyl-indan-4-carbaldehyde Step-I:synthesis of 4-Methoxy-5-methyl-indan-1-one

To a suspension of 4-Hydroxy-5-methyl-indan-1-one (50.0 gm, 0.308 mole)and Potassium carbonate (127.0 gm, 0.928 mole) in Dimethylformamide (250ml), Dimethyl sulphate (90 ml, 0.928 mole) was added at 0° C. Thereaction mixture was heated at 60-65° C. and stirred for 16 hours. Thereaction mixture was poured into water (1 liter) and extracted withEthylacetate (3×250 ml). The organic layer was dried over Sodiumsulphate and distilled under vacuum to give 10.0 gm of crude productwhich was purified by column chromatography using Hexane as a mobilephase. The collected fractions were distilled under vacuum to give 45.0gm of desired product as a viscous oil.

Yield: 82.5%

NMR (400 mhz, DMSO-d₆): δ 7.30 (1H, d), 7.27 (1H, d), 3.84 (3H, s), 3.12(2H, t), 2.60-2.63 (2H, m), 2.31 (3H, s).

Step-II: Synthesis of 4-Methoxy-1,5-dimethyl-indan

To a suspension of Magnesium turning (2.72 gm, 0.113 mole) in Diethylether (40 ml), a solution of Methyl iodide (13.7 ml, 0.219 mole) inDiethyl ether (10 ml) was added slowly at 30-35° C. under nitrogenatmosphere. The reaction mixture was stirred for an hour at roomtemperature and then a solution of 4-Methoxy-5-methyl-indan-1-one (10.0gm, 0.0568 mole) in Diethyl ether (30 ml) was added at 0° C. Thereaction mixture was stirred for an hour at room temperature and thendilute Hydrochloric acid (50 ml) was added. It was extracted withEthylacetate (3×50 ml). The organic layer was dried over Sodiumsulphate, distilled under vacuum to give 10.0 gm of crude alcohol. Theobtained alcohol was taken with Triethyl silane (41.3 ml, 0.258 mole)and added Trifluoroacetic acid (100 ml) at 0° C. The reaction mixturewas stirred at 65-70° C. for 4 hours and poured into saturated Sodiumbicarbonate solution. It was extracted with Ethylacetate (2×100 ml),dried over Sodium sulphate, distilled under vacuum to give a crude masswhich was purified by column chromatography using Hexane as a mobilephase. The collected fractions were distilled under vacuum to give 5.0gm of desired product as a viscous oil.

Yield: 50%

NMR (400 mhz, DMSO-d₆): δ 6.96 (1H, d), 6.81 (1H, d), 3.69 (3H, s),3.04-3.10 (1H, m), 2.87-2.94 (1H, m), 2.73-2.81 (1H, m), 2.21-2.28 (1H,m), 2.15 (3H, s), 1.46-1.55 (1H, m), 1.20 (3H, d).

Step-III: synthesis of 7-Methoxy-3,6-dimethyl-indan-4-carbaldehyde

It is prepared using procedure same as described for step-V of method-1for preparation of intermediate 1.

Yield: 43.1%

NMR (400 mhz, DMSO-d₆): δ 9.98 (1H, s), 7.52 (1H, s), 3.86 (3H, s),3.76-3.79 (1H, m), 2.89-3.08 (2H, m), 2.12-2.21 (4H, m), 1.79-1.84 (1H,m), 1.12 (3H, d).

4: Preparation of7-Methoxy-6-methyl-2-(4-nitro-phenoxy)-indan-4-carbaldehyde Step-I:synthesis of 2-Bromo-4-methoxy-5-methyl-indan-1-one

To a stirred solution of 4-Methoxy-5-methyl-indan-1-one (5.0 gm, 0.0284mole) in Acetic acid (65 ml) and Hydrobromic acid (1 ml), a solution ofBromine (1.47 ml, 0.0284 mole) in 5 ml Acetic acid was added at 10-20°C. The reaction mixture was stirred at 20-25° C. for an hour. Then itwas poured into saturated solution of Sodium bicarbonate and extractedwith Diethyl ether (3×100 ml). The organic layer was dried over Sodiumsulphate, distilled under vacuum to give crude product which waspurified over column chromatography using Ethyl acetate:Hexane (5:95) asa mobile phase. The collected fractions were distilled to give 3.2 gm ofdesired product as a viscous oil.

Yield: 44.2

NMR (400 mhz, DMSO-d₆): δ 7.44 (1H, d), 7.38 (1H, d), 5.00-5.03 (1H, m),3.89-3.97 (1H, m), 3.84 (3H, s), 3.31-3.36 (1H, merged with water peakpresent in DMSO-d₆), 2.33 (3H, s).

Step-II: synthesis of 4-Methoxy-5-methyl-2-(4-nitro-phenoxy)-indan-1-one

To a stirred solution of 2-Bromo-4-methoxy-5-methyl-indan-1-one (2.0 gm,0.0078 mole) in Dimethylformamide (15 ml), added Sodium salt of4-Nitrophenol (1.27 gm, 0.0078 mole) at 10-15° C. After 2 hours stirringat 25-28° C., reaction mixture was poured into water (50 ml). Theseparated solid was filtered, washed with hexane and dried under vacuumto give 1.8 gm of desired product as a solid

Yield: 73.4%

NMR (400 mhz, DMSO-d₆): δ 8.26 (2H, d), 7.30-7.43 (4H, m), 5.58 (1H,dd), 3.89-3.95 (1H, m), 3.85 (3H, s), 3.10-3.15 (1H, m), 2.34 (3H, s).

Step-III: Synthesis of 4-Methoxy-5-methyl-2-(4-nitro-phenoxy)-indan

To a mixture of 4-Methoxy-5-methyl-2-(4-nitro-phenoxy)-indan-1-one (1.8gm, 0.0057 mole) and Triethyl silane (9.0 ml, 0.0564 mole),Trifluoroacetic acid (18 ml) was added at 20-25° C. The reaction mixturewas heated to 60-65° C. for 3 hours and then poured into saturatedSodium bicarbonate solution. It was extracted with Ethylacetate (2×100ml), dried over Sodium sulphate, distilled under vacuum to give a crudeproduct which was purified by column chromatography using Ethylacetate:Hexane (2:98) as a mobile phase. The collected fractions weredistilled under vacuum to give 1.2 gm of desired product as a solid.

Yield: 69.7%

NMR (400 mhz, DMSO-d₆): δ 8.22 (2H, d), 7.18 (2H, d), 7.02 (1H, d), 6.91(1H, d), 5.40-5.43 (1H, m), 3.71 (3H, s), 3.38-3.51 (2H, m), 2.99-3.10(2H, m), 2.18 (3H, s).

Step-IV: Synthesis of7-Methoxy-6-methyl-2-(4-nitro-phenoxy)-indan-4-carbaldehyde

It is prepared using procedure same as described for step-V of method-1for preparation of intermediate 1.

Yield: 93.1%

NMR (400 mhz, DMSO-d₆): δ 9.95 (1H, s), 8.19 (2H, d), 7.61 (1H, s), 7.19(2H, d), 5.47-5.50 (1H, m), 3.88 (3H, s), 3.55-3.70 (2H, m), 3.42-3.46(1H, m), 3.17-3.21 (1H, m), 2.25 (3H, s).

MASS: 328 (M⁺+1)

5: Preparation of 7-Methoxy-2,2,6-trimethyl-indan-4-carbaldehyde Step-I:Preparation of 4-Methoxy-2,2,5-trimethyl-indan-1-one

To a suspension of 60% Sodium hydride (2.72 gm, 0.068 mole) in 30 mlTetrahydrofuran, a solution of 4-Methoxy-5-methyl-indan-1-one (10.0 gm,0.0568 mole) in Tetrahydrofuran (30 ml) was added at 0-5° C.; further tothis, Methyl iodide (9.09 ml, 0.146 mole) was added at 0° C. Thereaction mixture was stirred for 2 hours, then water (100 ml) was addedand extracted with Ethylacetate (2×100 ml). The Ethylacetate layer wasdried over Sodium sulphate and evaporated to give a crude mass which waspurified over column chromatography using Ethyl acetate:Hexane (3:97) asmobile phase. The fractions were distilled under vacuum to give 3.0 gmof desired product as viscous oil.

Yield: 25.88%

NMR (400 mhz, DMSO-d₆): δ 7.31 (1H, d), 7.29 (1H, d), 3.83 (3H, s), 3.03(2H, s), 2.30 (3H, s), 1.14 (6H, s).

Step-II: Preparation of 4-Methoxy-2,2,5-trimethyl-indan

It is prepared using procedure same as described for step-III ofpreparation of intermediate 4.

Yield: 92.3%

NMR (400 mhz, DMSO-d₆): δ 6.99 (1H, d), 6.79 (1H, d), 3.68 (3H, s), 2.70(2H, s), 2.62 (2H, s), 2.14 (3H, s), 1.10 (6H, s).

Step-III: Preparation of 7-Methoxy-2,2,6-trimethyl-indan-4-carbaldehyde

It is prepared using procedure same as described for step-V for method-1preparation of intermediate 1.

Yield: 50.8%

NMR (400 mhz, DMSO-d₆): δ 9.95 (1H, s), 7.51 (1H, s), 3.83 (3H, s), 2.98(2H, s), 2.80 (2H, s), 2.21 (3H, s), 1.12 (6H, s).

6: Preparation of7-Methoxy-6-(pyrrolidine-1-carbonyl)-indan-4-carbaldehyde Step-I:Preparation of 4-Methoxy-indan-5-carboxylic acid

To a clear solution of 4-Methoxy-indan-5-carbaldehyde (11.5 gm, 0.065mole) in Dichloromethane (100 ml), Sulphamic acid (19.0 gm, 0.196 mole)was added at 25-28°. A solution of Sodium chlorite (15.28 gm, 0.169mole) in water (50 ml) was added at 5-10° C. The reaction mixture wasstirred for 5 hours at 25-28° C. Finally the reaction mixture was pouredinto water (200 ml) and extracted with Dichloromethane (2×200 ml). Theorganic layer was dried over Sodium sulphate, distilled under vacuum togive 12.0 gm of desired product as a viscous oil.

Yield: 96.0%

MASS: 191 (M⁺−1)

Step-II: Preparation of (4-Methoxy-indan-5-yl)-pyrrolidin-1-yl-methanone

To a clear solution of 4-Methoxy-indan-5-carboxylic acid (12.0 gm,0.0625 mole) in Tetrahydrofuran (60 ml), Carbonyl-diimidazole (13.24 gm,0.0812 mole) was added at 25-28° C. The reaction mixture was heated to65-70° C. and stirred for 2 hours to the reaction mixture, a solution ofPyrrolidine (5.74 ml, 0.0687 mole) in Tetrahydrofuran (20 ml) was addedat 10-15° C. The reaction mixture was poured into water (200 ml) andextracted with Ethylacetate (2×100 ml). The organic layer was dried overSodium sulphate, distilled under vacuum and purified by columnchromatography using Ethyl acetate:Hexane (20:80) as mobile phase. Thefractions were distilled under vacuum to give 6.0 gm of desired productas a viscous oil.

Yield: 39.2%

NMR (400 mhz, DMSO-d₆): δ 6.98 (2H, s), 3.74 (3H, s), 3.44 (2H, t), 3.13(2H, t), 2.85-2.94 (4H, m), 2.01-2.06 (2H, m), 1.75-1.88 (4H, m).

Step-III: Preparation of7-Methoxy-6-(pyrrolidine-1-carbonyl)-indan-4-carbaldehyde

It is prepared using procedure same as described for step-V of method-1for preparation of intermediate 1.

Yield: 71.7%

NMR (400 mhz, DMSO-d₆): δ 10.0 (1H, s), 7.60 (1H, s), 3.88 (3H, s),3.46-3.49 (2H, m), 3.16-3.24 (4H, m), 2.97 (2H, t), 2.05-2.13 (2H, m),1.80-1.92 (4H, m).

MASS: 298 (M⁺+1)

7: Preparation of 7-Methoxy-6-(4-methoxy-phenyl)-indan-4-carbaldehydeStep-I: Preparation of 6-Bromo-7-methoxy-indan-4-carbaldehyde

To a solution of 4-Hydroxy-indane (10.0 gm, 0.0746 mole) andDiisopropylamine (1 ml) in Dichloromethane (100 ml), N-Bromo succinimide(13.28 gm, 0.0746 mole) was added slowly at 5-15° C. The reactionmixture was stirred for 20 hours. Dichloromethane was distilled andresidue was partition between water (100 ml) and Diethylether (200 ml).Diethylether was distilled under vacuum to give crude solid (14.4 gm).solid was dissolved in Trifluoroacetic acid (100 ml) and added Hexamine(8.4 gm, 0.06 mole) at 25-28° C. Further the reaction mixture was heatedto 85-90° C. for 4 hours. The reaction mixture was poured into saturatedSodium bicarbonate solution and extracted with Ethylacetate (3×100 ml).The organic layer was dried over Sodium sulphate, distilled under vacuumto give crude mass which was purified over column chromatography usingEthyl acetate:Hexane (3:97) as mobile phase. The collected fractionswere distilled to give 7.34 gm of aldehyde. Finally to the solution ofobtained aldehyde (7.34 gm, 0.0304 mole) in Dimethylformamide (30 ml),Potassium carbonate (6.3 gm, 0.0463 mole) was added and stirred for anhour. To the reaction mixture, Methyl iodide (2.9 ml, 0.0463 mole) wasadded at 0-5° C. and stirred at 20-25° C. for 4 hours. Then, the water(100 ml) was added and extracted with Diethyl ether (3×100 ml). TheDiethyl ether was dried over Sodium sulphate and distilled to give acrude product which was purified over column chromatography using Ethylacetate:Hexane (2:98). The fractions were distilled under vacuum to give1.06 gm of title compound as a solid

Yield: 5.5%

NMR (400 mhz, DMSO-d₆): δ 9.97 (1H, s), 7.91 (1H, s), 3.91 (3H, s), 3.16(2H, t), 3.03 (2H, t), 2.04-2.12 (2H, m).

Step-II: Preparation of7-Methoxy-6-(4-methoxy-phenyl)-indan-4-carbaldehyde

To a suspension of 6-Bromo-7-methoxy-indan-4-carbaldehyde (0.2 gm,0.00078 mole), 4-Methoxyphenyl boronic acid (0.122 gm, 0.0008 mole) andPotassium carbonate (0.27 gm, 0.0019 mole) in Toluene (5 ml) and water(5 ml), Tetrakis (triphenylphosphine) palladium(0) (2 mg) was and heatedto 85-90° C. and stirred for 6 hrs. Toluene was distilled off and theobtained residue was dissolved in Diethyl ether (50 ml). Further it waswashed with water (20 ml) and ether was distilled under vacuum to give acrude mass which was purified by column chromatography using Ethylacetate:Hexane (1:99) as a mobile phase. The fractions were distilled togive 50 mg of desired product as a solid.

Yield: 22.7%

NMR (400 mhz, DMSO-d₆): δ 10.05 (1H, s), 7.65 (1H, s), 7.45 (2H, d),7.01 (2H, d), 3.80 (3H, s), 3.61 (3H, s), 3.22 (2H, t), 2.99 (2H, t),2.07-2.15 (2H, m).

MASS: 283 (M⁺+1)

8: Preparation of 6-Chloro-7-methoxy-indan-4-carbaldehyde Step-I:Preparation of 5-Chloro-indan-4-ol

To a clear solution of Indan-4-ol (40.0 gm, 0.297 mole) andDiisopropylamine (4.29 ml, 0.029 mole) in Dichloromethane (140 ml), asolution of Sulfuryl chloride (21.76 ml, 0.267 mole) in Dichloromethane(20 ml) was added at 0-5° C. The reaction mixture was stirred for 15hours at 20-25° C. and poured into water (200 ml). Further it wasextracted with Ethylacetate (2×200 ml). The organic layer was dried overSodium sulphate, distilled under vacuum to give crude solid which waspurified by column chromatography using Ethyl acetate:Hexane (2:98) asmobile phase. The collected fractions were distilled to give 5.7 gm ofdesired product as a solid.

Yield: 11.4%

NMR (400 mhz, DMSO-d₆): δ 9.28 (1H, s), 7.08 (1H, d), 6.80 (1H, d),2.79-2.83 (4H, m), 1.97-2.04 (2H, m).

Step-II: Preparation of 6-Chloro-7-hydroxy-indan-4-carbaldehyde

It is prepared using procedure same as described for step-V of method-1for preparation of intermediate 1.

Yield: 81.2%

NMR (400 mhz, DMSO-d₆): δ 9.85 (1H, s), 7.67 (1H, s), 3.14 (2H, t), 2.81(2H, t), 1.99-2.04 (2H, m).

Step-III: Preparation of 6-Chloro-7-methoxy-indan-4-carbaldehyde

It is prepared using procedure same as described for step-VI of method-1for preparation of intermediate 1.

Yield: 55.7%

NMR (400 mhz, DMSO-d₆): δ 10.04 (1H, s), 7.84 (1H, s), 3.98 (3H, s),3.24 (2H, t), 3.08 (2H, t), 2.11-2.19 (2H, m).

MASS: 211 (M⁺+1)

9: Preparation of 7-Methoxy-6-methyl-indan-4-ol

The stirred solution of 7-methoxy-6-methyl-indan-4-carbaldehyde (1.0 gm,0.0060 mole) in Methanol (20 ml), Sulphuric acid (0.6 ml) was added atroom temperature. To the reaction mixture, 30% Hydrogen peroxide (1.6ml) was added and stirred for 1 hour at 0° C. Methanol was distilledunder vacuum and the residue was dissolved in Ethylacetate (50 ml),further ethyl acetate layer was washed with water and evaporated to givea crude product, which upon triturating with Hexane give 600 mg titlecompound as a solid.

Yield: 56%

NMR (400 mhz, DMSO-d₆): δ 8.78 (1H, s), 6.37 (1H, s), 3.58 (3H, s), 2.81(2H, t), 2.69 (2H, t), 2.09 (3H, s), 1.95-1.98 (2H, m).

MASS: 177 (M⁺−1)

Following Compounds were Prepared Using the Procedure Mentioned inReaction Scheme as Depicted Above:

TABLE 1 Compd ¹H-NMR (400 MHz, IR (KBr, No. NAME DMSO-d₆)$ MASS CM⁻¹) 13-[4-(7-Hydroxy-indan-4- δ12.27(1H, bs), 8.77(1H, bs), 315 (M⁺ − 1)3215, 1702, yloxy)-3,5-dimethyl- 6.42(1H, d), 6.15(1H, d), 4.10(2H,1653, 1599 pyrazol-1-yl]-propionic t), 2.84(2H, t), acid 2.71-2.78(4H,m), 1.98-2.04(5H, m), 1.88(3H, s) 2 3-[4-(1H-Indol-5- δ 298 (M⁺ + 1)3392, 1710, ylmethyl)-3,5-dimethyl- 12.33(1H, bs), 10.93(1H, s), 1558,1507 pyrazol-1-yl]-propionic 7.21-7.27(3H, m), acid 6.85(1H, dd),6.31(1H, t), 4.10(2H, t) 3.69(2H, s), 2.71(2H, t), 2.17(3H, s), 1.99(3H,s). 3 7-[3,5-Dimethyl-1-(1H- δ 325 (M⁺ − 1) 3313, 1589,tetrazol-5-ylmethyl)-1H- 8.85(1H, s), 6.44(1H, d), 1553, 1484pyrazol-4-yloxy]-indan-4- 6.21(1H, d), ol 5.55(2H, s), 2.84(2H, t),2.76(2H, t), 2.11(3H, s), 2.00-2.06(2H, m), 1.88(3H, s). 4 :7-{3,5-Dimethyl-1-[2- δ.8.74(1H, bs), 6.42(1H, d), 339 (M⁺ − 1) 3310,1646, (1H-tetrazol-5-yl)-ethyl]- 6.09(1H, d), 1553, 14861H-pyrazol-4-yloxy}- 4.33(2H, t), 3.37(2H, t), indan-4-ol 2.74-2.82(4H,m), 2.01-2.05(2H, m), 1.89(3H, s), 1.87(3H, s). 5{2-[4-(7-Hydroxy-indan- δ 358 (M⁺ − 1) 3346, 1660,4-yloxy)-3,5-dimethyl- 12.65(1H, bs), 8.82(1H, s), 1553, 1491pyrazol-1-yl]-acetyl 8.26(1H, t), amino}-acetic acid 6.43(1H, d),6.21(1H, d), 4.69(2H, s), 3.79(2H, d), 2.85(2H, t), 2.76(2H, t),1.99-2.06(5H, m), 1.88(3H, s). 6 : 2-[4-(7-Hydroxy-indan- δ12.48(1H,bs), 8.80(1H, bs), 368 (M⁺ − 1) 3226, 1712, 4-yloxy)-3,5-dimethyl-6.44(1H, d), 1620, 1555 pyrazol-1-yl]-N-(1H- 6.21(1H, d), 5.03(2H, s),tetrazol-5-yl)-acetamide 2.87(2H, t), 2.77(2H, t), 1.99-2.07(5H, m),1.89(3H, s). 7 3-[4-(7-Hydroxy-indan-4- For major isomer 368.99 (M⁺ − 1)3108, 1708, yloxy)-3-thiophen-2-yl- δ12.41(1H, s), 9.00(1H, s), 1564,1486 pyrazol-1-yl]-propionic 7.55(1H, s), acid 7.44(1H, d), 7.29(1H, d),And 7.04-7.06(1H, m), 3-[4-(7-Hydroxy-indan-4- 6.46-6.54(2H, m),4.24(2H, t), yloxy)-5-thiophen-2-yl- 2.73-2.84(6H, m),pyrazol-1-yl]-propionic 1.96-2.06(2H, m). acid 8 7-[1-(1H-Tetrazol-5-For major isomer 379 (M⁺ − 1) 3243, 1732, ylmethyl)-3-thiophen-2-δ9.07(1H, s), 7.69(1H, s), 1550, 1483 yl-1H-pyrazol-4-yloxy]- 7.47(1H,dd), 7.35(1H, dd), indan-4-ol 7.06-7.08(1H, m), 6.63(1H, d), And6.53(1H, d), 7-[1-(1H-Tetrazol-5- 5.67(2H, s), 2.77-2.86(4H,ylmethyl)-5-thiophen- m), 2-yl-1H-pyrazol- 1.99-2.06(2H, m)4-yloxy]-indan-4-ol 9 3-[4-(7-Hydroxy-6- δ12.31(1H, bs), 8.11(1H, s),327 (M⁺ − 1) 3388, 1686, methyl-indan-4- 6.41(1H, s), 1616, 1489ylmethyl)-3,5-dimethyl- 4.09(2H, t), 3.43(2H, s),pyrazol-1-yl]-propionic 2.68-2.77(6H, m), 2.09(3H, s), acid 2.03(3H, s),1.94-1.99(2H, m) 1.91(3H, s). 10 5-[4-(7-Hydroxy-indan-4- δ8.82(1H, bs),6.41(1H, d), 339 (M⁺ − 1) 3143, 1581, yloxy)-3,5- 6.15(1H, d), 5.22(1H,s), 1546, 1483 dimethyl-pyrazol-1- 5.01(2H, s), 2.82(2H, t),ylmethyl]-1H-pyrazol- 2.74(2H, t), 3-ol 1.93-2.06(5H, m), 1.84(3H, s).11 2-[4-(7-Hydroxy-6- δ12.86(1H, bs), 8.13(1H, s), 6.44(1H, 312.9 (M⁺− 1) 3392, 1730, methyl-indan-4- s), 1569, 1485 ylmethyl)-3,5-dimethyl-4.81(2H, s), 3.45(2H, s), pyrazol-1-yl]-acetic acid 2.69-2.77(4H, m),1.89-2.03(11H, m). 12 7-[1-(2-Hydroxy-ethyl)- δ8.11(1H, s), 6.43(1H, s),301 (M⁺ + 1) 3320, 3167, 3,5-dimethyl-1H-pyrazol- 4.80(1H, t), 3.95(2H,t), 3.63(2H, 1570, 1481 4-ylmethyl]-5-methyl- q), 3.43(2H, s),indan-4-ol 2.69-2.77(4H, m), 2.08(3H, s), 2.03(3H, s), 1.92-1.99(5H, m).13 [4-(1H-Indol-5-ylmethyl)- δ12.97(1H, bs), 10.95(1H, s), 284 (M⁺ + 1)3401, 1712, 3,5-dimethyl-pyrazol-1- 7.25-7.27(2H, m), 1640, 1470yl]-acetic acid 7.22(1H, s), 6.86(1H, dd), 6.31(1H, s), 4.78(2H, s),3.71(2H, s), 2.10(3H, s), 1.99(3H, s). 14 3-[4-(7-Methoxy-6- δ12.29(1H,bs), 6.49(1H, s), 342.9 (M⁺ + 1) 2941, 1729, methyl-indan-4- 4.10(2H,t), 1557, 1475 ylmethyl)-3,5-dimethyl- 3.64(3H, s), 3.48(2H, s),2.86(2H, pyrazol-1-yl]-propionic t), acid 2.68-2.75(4H, m), 2.10(3H, s),2.08(3H, s), 1.96-2.03(2H, m), 1.92(3H, s). 15 7-[3,5-Dimethyl-1-(1H-δ8.13(1H, bs), 6.43(1H, s), 337 (M⁺ − 1) 3233, 1542,tetrazol-5-ylmethyl)- 5.53(2H, s), 3.46(2H, s), 2.75(2H, 1488, 14531H-pyrazol-4- t), 2.70(2H, t), ylmethyl]-5-methyl- 2.17(3H, s), 2.03(3H,s), indan-4-ol 1.91-1.99(5H, m). 16 7-[3,5-Diisopropyl-1-(1H- δ8.12(1H,s), 6.25(1H, s), 393 (M⁺ − 1) 2962, 1668, tetrazol-5- 5.56(2H, s),3.59(2H, s), 1599, 1478 ylmethyl)-1H-pyrazol-4- 3.19-3.20(1H, m),ylmethyl]-5-methyl- 2.77-2.79(4H, m), indan-4-ol 2.65-2.68(1H, m),1.94-2.10(5H, m), 1.07(6H, d), 1.02(6H, d). 17 3-[3,5-Dicyclopropyl-4-δ12.36(1H, bs), 8.80(1H, s), 367 (M⁺ − 1) :3213, 2949, (7-hydroxy-indan-6.43(1H, d), 1702, 1482 4-yloxy)-pyrazol-1- 6.14(1H, d), 4.22(2H, t),yl]-propionic acid 2.87(2H, t), 2.75-2.79(4H, m), 2.02-2.07(2H, m),1.67-1.71(1H, m), 1.45-1.49(1H, m), 0.72-0.76(2H, m), 0.62-0.67(6H, m).18 3-[4-(7-Hydroxy-6- δ12.39(1H, bs), 8.11(1H, s), 383 (M⁺ − 1) 2963,1716, methyl-indan-4- 6.23(1H, s), 4.21(2H, t), 3.55(2H, 1584, 1481ylmethyl)-3,5- s), 3.04-3.11(1H, m), diisopropyl-pyrazol-1-yl]-2.69-2.79(6H, m), propionic acid 2.60-2.67(1H, m), 1.93-2.03(5H, m),1.12(6H, d), 1.04.(6H, d). 19 [3,5-Diethyl-4-(7- δ8.14(1H, s), 6.39(1H,s), 341 (M⁺ − 1) 3398, 2931, hydroxy-6-methyl- 4.77(2H, s), 3.48(2H,merged 1718, 1476 indan-4-ylmethyl)- with peak of water presentpyrazol-1-yl]-acetic in DMSO-d₆), acid 2.68-2.77(4H, m), 2.43(2H, q),2.30(2H, q), 1.94-2.01(5H, m), 1.00(3H, t), 0.90(3H, t). ¹H-NMR (400MHz, CD₃OD) δ6.66(1H, s), 4.83(2H, s), 3.59(2H, s), 2.75-2.83(4H, m),2.51(2H, q), 2.42(2H, q), 1.91-2.07(5H, m), 1.05(3H, t), 0.97(3H, t). 203-[3,5-Diethyl-4-(7- δ8.13(1H, s), 6.37(1H, s), 355 (M⁺ − 1) 3380, 2951,hydroxy-6-methyl-indan- 4.12(2H, t), 3.47(2H, s), 1707, 15544-ylmethyl)-pyrazol-1-yl]- 2.72-2.76(6H, m), 2.51(2H, merged propionicacid with DMSO-d6 peak), 2.31(2H, q), 1.97-2.01(5H, m), 1.00(3H, t),0.93(3H, t). ¹H-NMR (400 MHz, CD₃OD) δ6.42(1H, s), 4.26(2H, t), 3.56(2H,s), 2.79-2.83(4H, m), 2.75(2H, t), 2.57(2H, q), 2.42(2Hq), 1.98-2.07(5H,m), 1.04(3H, t), 0.99(3H, t). 21 7-[3,5-Diethyl-1-(1H- δ8.14(1H, bs),6.39(1H, s), 365 (M⁺ − 1) 3464, 2951, tetrazol-5-ylmethyl)- 5.77(2H.s),3.49(2H, s), 1578, 1477 1H-pyrazol-4- 2.71-2.78(4H, m),ylmethyl]-5-methyl- 2.58-2.61(2H, q), 2.31(2H, q), indan-4-ol1.92-2.07(5H, m), 0.98(3H, t), 0.92(3H, t). 22 [3,5-Dicyclopropyl-4-(7-δ8.82(1H, s), 6.44(1H, d), 355 (M⁺ + 1) 3305, 1718,hydroxy-indan-4-yloxy)- 6.16(1H, d), 4.81(2H, s), 1579, 1483pyrazol-1-yl]-acetic acid 2.88(2H, t), 2.78(2H, t), 1.99-2.07(2H, m),1.45-1.58(2H, m), 0.58-0.70(8H, m). 23 3-[3,5-Diethyl-4-(1H- δ12.35(1H,bs), 10.94(1H, s), 326 (M⁺ + 1) 3347, 1706, indol-5-ylmethyl)-7.25-7.27(2H, m), 7.21(1H, s), 1554, 1441 pyrazol-1-yl]- 6.85(1H, d),6.31(1H, s), 4.13(2H, propionic acid t), 3.73(2H, s), 2.76(2H, t),2.59(2H, q), 2.38(2H, q), 1.03(3H, t), 0.96(3H, t). 24 2-[4-(1H-Indol-5-δ10.94(1H, s), 270 (M⁺ + 1) 3229, 2924, ylmethyl)-3,5-dimethyl-7.25-7.27(2H, m), 1571, 1464 pyrazol-1-yl]-ethanol 7.22(1H.s), 6.86(1H,d), 6.31(1H, t), 4.82(1H, t), 3.96(2H, t), 3.70(2H, s), 3.64(2H, q),2.16(3H, s), 2.00(3H, s). 25 [4-(7-Hydroxy-indan-4- δ8.84(1H, bs),6.44(1H, d), 301 (M⁺ − 1) 3219, 1732, yloxy)-3,5-dimethyl- 6.19(1H, d),4.70(2H, s), 1594, 1479 pyrazol-1-yl]- 2.86(2H, t), 2.77(2H, t), aceticacid 1.98-2.06(5H, m), 1.88(3H, s). 26 3-[4-(6-Chloro-7- δ12.33(1H, bs),9.04(1H, s), 375 (M⁺ − 1) 3394, 1696, hydroxy-indan-4- 6.52(1H, s),1579, 1469 ylmethyl)-3,5-diethyl- 4.14(2H.t), 3.50(2H, s),pyrazol-1-yl]-propionic 2.73-2.83(6H, m), 2.52(2H, merged acid withDMSO-d6 peak), 2.30(2H, q), 1.97-2.04(2H, m), 0.99(3H, t), 0.93(3H, t).27 [4-(6-Chloro-7-hydroxy- δ9.05(1H, s), 6.55(1H, s), 361 (M⁺ − 1) 3408,2952, indan-4-ylmethyl)-3,5- 4.80(2H.s), 3.53(2H, s), 1719, 1475diethyl-pyrazol-1-yl]- 2.76-2.84(4H, m), 2.52(2H, merged acetic acidwith DMSO-d6 peak), 2.30(2H, q), 1.97-2.05(2H, m), 1.00(3H, t), 0.91(3H,t). 28 3-{4-[7-Hydroxy-6- 1H-NMR (400 MHz, 410 (M⁺ − 1) 2958, 1711,(pyrrolidine-1-carbonyl)- CDCl3) δ11.03(1H, bs) 1563, 1432 indan-4-6.71(1H, s), 4.25(2H, t), ylmethyl]-3,5-dimethyl- 3.51(2H.s),pyrazol-1-yl}- 3.48-3.52(4H, m), propionic acid 2.91-2.96(4H, m),2.84(2H, t), 2.08-2.16(8H, m), 1.86-1.90(4H, m). 29 3-[4-(6-Chloro-7- δ349 (M⁺ + 1) 2951, 1697, hydroxy-indan-4- 9.04(1H, s), 6.67(1H, s),1574, 1472 ylmethyl)-3,5-dimethyl- 4.11(2H, t), pyrazol-1-yl]-propionic3.47(2H, s), 2.80(2H, t), acid 2.69-2.76(4H, m), 2.11(3H, s),1.92-2.04(2H, m), 1.92(3H, s). 30 1-{2-[4-(7-Hydroxy-6- δ12.33(1H, bs),8.11(1H, s), 410 (M⁺ − 1) 3250, 1732, methyl-indan-4- 6.45(1H, s),4.93(2H, s), 1575, 1473 ylmethyl)-3,5-dimethyl- 4.22-4.25(1H, m),3.58(2H, t), pyrazol-1-yl]-acetyl}- 3.45(2H, s),pyrrolidine-2-carboxylic 2.69-2.77(4H, m), acid 1.83-2.16(15H, m). 317-[3,5-Dimethyl-1-(1H- δ8.08(1H, bs), 6.14(1H, s), 341 (M⁺ + 1) 3153,1556, tetrazol-5-ylmethyl)- 5.56(2H, s), 1487, 1421 1H-pyrazol-4-2.77-2.82(4H, m), 2.11(3H, s), yloxy]-5-methyl-indan-4- 1.97-2.09(5H,m), 1.88(3H, s). ol 32 [4-(7-Hydroxy-6-methyl- δ12.80(1H, bs), 8.19(1H,s), 369 (M⁺ − 1) 2965, 1733, indan-4-ylmethyl)-3,5- 6.35(1H, s),4.95(2H, s), 1550, 1483 diisopropyl-pyrazol-1-yl]- 3.68(2H, s), aceticacid 2.96-3.06(1H, m), 2.86-2.95(4H, m), 2.68-2.77(1H, m), 2.07-2.15(5H,m), 1.18(6H, d), 1.13(6H, d). 33 3-[4-(7-Hydroxy-6- δ8.11(1H, s),7.76(1H, d), 370 (M⁺ + 1) 3293, 1743, methyl-indan-4- 6.40(1H, s),4.08(2H, t), 1641, 1560 ylmethyl)-3,5-dimethyl- 3.76-3.81(1H, m),3.42(2H, s), pyrazol-1-yl]-N- 2.75(2H, t), isopropyl-propionamide2.69(2H, t), 2.51(2H, merged with DMSO-d6 peak), 2.07(3H, s), 2.02(3H,s), 1.90-1.99(5H, m), 0.98(6H, d). 34 [4-(7-Hydroxy-6-methyl- δ8.11(1H,s), 6.13(1H, s), 317 (M⁺ + 1) 3277, 1730, indan-4-yloxy)-3,5- 4.78(2H,s), 1575, 1483 dimethyl-pyrazol-1-yl]- 2.77-2.83(4H, m), acetic acid1.99-2.05(5H, m), 1.93(3H, s), 1.89(3H, s). 35 3-[4-(7-Hydroxy-6-δ12.38(1H, bs), 8.05(1H, s), 331 (M⁺ + 1) 3398, 1717,methyl-indan-4-yloxy)- 6.08(1H, s), 1580, 1486 3,5-dimethyl-pyrazol-1-4.10(2H, t), yl]-propionic acid 2.77-2.81(4H, m), 2.72(2H, t),1.97-2.08(8H, m), 1.88(3H, s). 36 4-[4-(7-Hydroxy-6- δ12.3(1H, bs),8.09(1H, s), 343 (M⁺ + 1) 3036, 1610, methyl-indan-4- 6.40(1H, s),3.92(2H, t), 3.44(2H, 1581, 1481 ylmethyl)-3,5-dimethyl- s), 2.74(2H,t), 2.69(2H, t), pyrazol-1-yl]-butyric acid 2.16(2H, t), 2.05(3H, s),2.02(3H, s), 1.83-1.98(7H, m). 37 3-[4-(7-Hydroxy-6- δ11.61(1H, bs),8.11(1H, s), 396 (M⁺ + 1) 2918, 1711, methyl-indan-4- 6.39(1H, s),4.20(2H, t), 1484, 1402 ylmethyl)-3,5-dimethyl- 3.42(2H, s), 2.91(2H,t), 2.72(2H, t), pyrazol-1-yl]-N-(1H- 2.64(2H, t), 2.10(3H, s),tetrazol-5-yl)- 1.98(3H, s), 1.87-1.91(5H, m). propionamide 385-[4-(7-Hydroxy-6- δ12.39(1H, s), 8.14(1H, s), 355 (M⁺ + 1) 3150, 1793,methyl-indan-4- 6.41(1H, s), 5.17(2H, s), 1483, 1434ylmethyl)-3,5-dimethyl- 3.46(2H, s), 2.74(2H, t), 2.68(2H, t),pyrazol-1-ylmethyl]-3H- 2.12(3H, s), 2.02(3H, s), [1,3,4]oxadiazol-2-one1.91-1.99(5H, m). 39 7-{3,5-Dimethyl-1-[2- δ6.34(1H, s), 4.40(2H, t),353 (M⁺ + 1) 3330, 1599, (1H-tetrazol-5- 3.43(2H, s), 3.37(2H, t),2.74(2H, 1548, 1441 yl)-ethyl]-1H-pyrazol-4- t), 2.63(2H, t), 2.04(3H,s), ylmethyl}- 1.99(3H, s), 1.91-1.96(5H, m). 5-methyl-indan-4-ol 40{2-[4-(7-Hydroxy-6- δ12.64(1H, bs), 8.20(1H, t), 370 (M⁺ − 1) 3283,2946, methyl-indan-4- 8.11(1H, s), 6.44(1H, s), 1667, 1562ylmethyl)-3,5-dimetyl- 4.67(2H, s), 3.78(2H, d), 3.45(2H, pyrazol-1-yl]-s), acetylamino}-acetic acid 2.69-2.77(4H, m), 2.03(6H, s),1.91-1.99(5H, m). 41 5-[4-(7-Hydroxy-6- δ9.43(1H, bs), 8.12(1H, s), 353(M⁺ + 1) 2948, 1589, methyl-indan-4- 6.40(1H, s), 1476, 1442ylmethyl)-3,5-dimethyl- 5.14(1H, s), 4.99(2H, s),pyrazol-1-ylmethyl]-1H- 3.44(2H, s), 2.74(2H, t), 2.69(2H, t),pyrazol-3-ol 2.08(3H, s), 2.02(3H, s), 1.91-1.98(5H, m). 425-[3,5-Diethyl-4-(7- δ12.41(1H, s), 8.14(1H, s), 383 (M⁺ + 1) 3475,2968, hydroxy-6-methyl- 6.37(1H, s), 5.20(2H, s), 1799, 1444indan-4-ylmethyl)- 3.49(2H, s), pyrazol-1-ylmethyl]- 2.69-2.77(4H, m),2.53(2H, merged 3H-[1,3,4]oxadiazol- with DMSO-d6 2-one peak), 2.31(2H,q), 1.91-2.01(5H, m), 0.99(3H, t), 0.92(3H, t). 43 5-{2-[4-(7-Hydroxy-6-δ12.09(1H, s), 8.10(1H, s), 369 (M⁺ + 1) 3370, 2958, methyl-indan-4-6.39(1H, s), 4.21(2H, t), 3.42(2H, 1788, 1580 ylmethyl)-3,5-dimethyl-s), 2.97(2H, t), 2.74(2H, t), pyrazol-1-yl]-ethyl}-3H- 2.66(2H, t),2.08(3H, s), [1,3,4]oxadiazol-2-one 2.05(3H, s), 1.89-1.99(5H, m). 44{2-[3,5-Diethyl-4-(7- δ 400 (M⁺ + 1) 3363, 1707, hydroxy-6-methyl-indan-8.20(2H, m), 6.40(1H, s), 1676, 1552. 4-ylmethyl)-pyrazol-1-yl]-4.79(2H, s), acetylamino}-acetic acid 3.81(2H, d), 3.49(2H, s),2.71-2.78(4H, m), 2.47(2H, merged with DMSO-d6 peak), 2.32(2H, q),1.85-2.01(5H, m), 1.01(3H, t), 0.92(3H, t). 45 6-[4-(7-Hydroxy-6-δ12.41(1H, s), 8.12(1H, s), 379 (M⁺ + 1) 2928, 1694, methyl-indan-4-6.42(1H, s), 1610, 1573. ylmethyl)-3,5-dimethyl- 5.13(1H, s), 4.95(2H,s), pyrazol-1-ylmethyl]-2- 3.49(2H, s), methyl-3H-pyrimidin-4-2.67-2.77(4H, m), 2.26(3H, s), one 2.03(6H, s), 1.94-1.99(5H, m). 463-[4-(7-Hydroxy-6- δ8.15(1H, s), 6.44(1H, s), 353 (M⁺ − 1) 3424, 1751,methyl-indan-4- 5.14(2H, s), 3.46(2H, s), 1491, 1443.ylmethyl)-3,5-dimethyl- 2.68-2.77(4H, m), 2.13(3H, s),pyrazol-1-ylmethyl]- 2.03(3H, s), 1.87-1.99(5H, m).[1,2,4]oxadiazol-5-ol 47 7-(1-Benzyl-3,5- δ8.12(1H, s) 347 (M⁺ + 1)2944, 1608, dimethyl-1H-pyrazol-4- 7.22-7.33(3H, m), 1569, 1484.ylmethyl)-5-methyl- 7.02-7.04(2H, m), 6.40(1H, s), indan-4-ol 5.20(2H,s), 3.47(2H, s), 2.74(2H, t), 2.68(2H, t), 2.02(3H, s), 2.00(3H, s),191-1.99(5H, m). 48 3-{4-[7-Hydroxy-6-(4- δ12.33(1H, bs), 8.22(1H, s),419 (M⁺ + 1) 3384, 2921, methyl-benzyl)-indan-4- 6.97-7.03(4H, m),6.44(1H, s), 1716, 1613. ylmethyl]-3,5-dimethyl- 4.06(2H, t), 3.73(2H,s), 3.41(2H, pyrazol-1-yl}-propionic s), 2.74(2H, t), acid 2.64-2.69(4H,m), 2.22(3H, s), 2.03(3H, s), 1.90-1.98(2H, m), 1.86(3H, s). 492-[4-(7-Hydroxy-6- δ12.77(1H, s), 8.11(1H, s), 327 (M⁺ − 1) 2949, 1708,methyl-indan-4- 6.43(1H, s), 4.98(1H, q), 1650, 1579.ylmethyl)-3,5-dimethyl- 3.45(2H, s), pyrazol-1-yl]-propionic2.68-2.76(4H, m), 2.05(3H, s), acid 2.02(3H, s), 1.91-1.98(5H, m),1.56(3H, d). 50 3-[4-(7-Hydroxy-6- δ8.11(1H, bs), 6.58(1H, s), 355 (M⁺− 1) 3426, 2985, isopropyl-indan-4- 4.08(2H, t), 1711, 1610.ylmethyl)-3,5-dimethyl- 3.45(2H, s), pyrazol-1-yl]-propionic3.13-3.22(1H, m), 2.74(2H, t), acid 2.63-2.68(4H, m), 2.10(3H, s),1.91-1.97(5H, m), 1.07(6H, d). 51 {4-[7-Hydroxy-6-(4- δ8.23(1H, s), 405(M⁺ + 1) 2926, 1710, methyl-benzyl)-indan-4- 6.95-7.01(4H, s), 6.51(1H,s), 1612, 1574. ylmethyl]-3,5-dimethyl- 4.69(2H, s),pyrazol-1-yl}-acetic acid 3.73(2H, s), 3.44(2H, s), 2.74(2H, t),2.68(2H, t), 2.22(3H, s), 1.91-1.97(5H, m), 1.87(3H, s). 523-{4-[6-(4-Fluoro- δ8.29(1H, s), 423 (M⁺ + 1) 2949, 1703,benzyl)-7-hydroxy-indan- 7.12-7.16(2H, m), 7.03(2H, t), 1604, 1569.4-ylmethyl]-3,5-dimethyl- 6.45(1H, s), pyrazol-1-yl}-propionic 4.06(2H,t), 3.77(2H, s), acid 3.42(2H, s), 2.75(2H, t), 2.64-2.69(4H, m),2.04(3H, s), 1.91-1.99(2H, m), 1.86(3H, s). 53 {4-[6-(4-Fluoro-benzyl)-δ8.30(1H, s), 407 (M⁺ − 1) 2943, 1711, 7-hydroxy-indan- 7.13-7.17(2H,m), 7.03(2H, t), 1603, 1575. 4-ylmethyl]-3,5- 6.52(1H, s),dimethyl-pyrazol-1-yl}- 4.59(2H, s), 3.77(2H, s) acetic acid 3.42(2H,s), 2.75(2H, t), 2.69(2H, t), 1.79-1.98(8H, m). 54 Sodium salt of4-[4-(7- δ6.26(1H, s), 3.86(2H, t), 341 (M⁺ − 1) 1650, 1554,Hydroxy-6-methyl-indan- 3.35(2H, s), 1469, 1410.4-ylmethyl)-3,5-dimethyl- 2.60-2.66(4H, m), 2.07(3H, s),pyrazol-1-yl]-butyric 1.92(3H, s), 1.90(3H, s), acid, 1.74-1.87(6H, m).55 Magnesium salt of 3-[4- δ8.16(1H, bs), 6.40(1H, s), 327 (M⁺ − 1)1678, 1612 (7-Hydroxy-6-methyl- 4.06(2H, t), 3.40(2H, s), 1573, 1480.indan-4-ylmethyl)-3,5- 2.63-2.76(4H, m), 2.47(2H, mergeddimethyl-pyrazol-1-yl]- with DMSO-d6 propionic acid peak), 2.07(3H, s),2.01(3H, s), 1.90-1.97(5H, m). 56 Sodium salt of 3-[4-(7- δ6.27(1H, s),4.00(2H, t), 327 (M⁺ − 1) 1650 Hydroxy-6-methyl-indan- 3.33(2H, s),1575, 1470, 4-ylmethyl)-3,5- 2.61-2.68(4H, m), 2.25(2H, t), 1410.dimethyl-pyrazol-1-yl]- 2.06(3H, s), 1.92(6H, s), propionic acid,1.76-1.86(2H, m). 57 3-{3,5-Diethyl-4-[6-(4- δ12.2(1H, bs), 8.29(1H, s),451 (M⁺ + 1) 3377, fluoro-benzyl)- 7.09-7.12(2H, m), 7.01(2H, t), 2970,1715, 7-hydroxy-indan-4- 6.37(1H, s), 4.09(2H, t), 3.75(2H, 1603.ylmethyl]-pyrazol-1-yl}- s), 3.45(2H, s), 2.76(2H, t), propionic acid2.67-2.72(4H, m), 2.44(2H, q), 2.23(2H, q), 1.92-1.98(2H, m), 0.93(3H,t), 0.83(3H, t). 58 3-[4-(7-Methoxy-6- δ6.50(1H, s), 385 (M⁺ + 1) 1666,methyl-indan-4- 4.07-4.13(4H, m), 3.66(3H, s), 1587, 1475,ylmethyl)-3,5-dimethyl- 3.58(2H, s), 2.87(2H, t), 1438pyrazol-1-yl]-3-oxo- 2.75(2H, t), 2.43(3H, s), 2.09(3H, propionic acidethyl ester s), 1.97-2.04(5H, m), 1.15(3H, t). 59 [3,5-Diethyl-4-(7-δ9.23(1H, s), 6.51(1H, s), 371 (M⁺ + 1) 3290, methoxy-6-methyl- 4.58(2H,s), 29521661, indan-4-ylmethyl)- 4.29-4.30(2H, d), 3.64(3H, s), 1540.pyrazol-1-yl]-acetic 3.52(2H, s), 2.87(2H, t), 2.76(2H, acid hydrazidet), 2.47(2H, merged with DMSO-d6 peak), 2.30(2H, q), 2.07(3H, s),1.97-2.04(2H, m), 1.00(3H, t), 0.90(3H, t). 60 N-Hydroxy-2-[4-(7-δ9.20(1H, bs), 6.52(1H, s), 343 (M⁺ + 1) 3468, 2947,methoxy-6-methyl-indan- 5.24(2H, s), 4.51(2H, s), 1666,4-ylmethyl)-3,5-dimethyl- 3.64(3H, s), 3.49(2H, s), 2.86(2H, t), 1587.pyrazol-1-yl]- 2.74(2H, t), 2.09(6H, s), acetamidine 1.98-2.05(2H, m),1.94(3H, s). 61 [4-(7-Methoxy-6-methyl- δ6.55(1H, s), 4.39(2H, q), 371(M⁺ + 1) 1758, indan-4-ylmethyl)-3,5- 3.65(3H, s), 3.62(2H, s), 1725,1483, dimethyl-pyrazol-1-yl]- 2.88(2H, t), 2.75(2H, t), 2.48(3H, s),1399. oxo-acetic acid ethyl 2.09(3H, s), ester 1.99-2.05(5H, m),1.30(3H, t). 62 [4-(7-Methoxy-6-methyl- δ6.53(1H, s), 384 (M⁺ + 1) 1688,indan-4-ylmethyl)-3,5- 3.63-3.65(7H, m), 1590, 1481,dimethyl-pyrazol-1-yl]- 3.53-3.56(6H, m), 2.87(2H, t), 1431.morpholin-4-yl- 2.74(2H, t), 2.22(3H, s), 2.09(3H, methanone s),1.96-2.04(5H, m). 63 1-(4-Chloro-phenyl)-4- δ7.54(4H, s), 6.59(1H, s),381 (M⁺ + 1) 2949, 1590, (7-methoxy-6-methyl- 3.65(3H, s), 1566, 1503.indan-4-ylmethyl)-3,5- 3.60(2H, s), 2.88(2H, t), dimethyl-1H-pyrazole2.79(2H, t), 2.21(3H, s), 2.12(3H, s), 1.98-2.05(5H, m). 642-(4-Methanesulfonyl- δ7.88(2H, d), 7.60(2H, d), 467 (M⁺ + 1) 29411723,phenyl)-1-[4-(7-methoxy- 6.51(1H, s), 4.58(2H, s), 1596, 1483.6-methyl-indan-4- 3.65(3H, s), 3.60(2H, s), 3.21(3H,ylmethyl)-3,5-dimethyl- s), 2.88(2H, t), 2.76(2H, t),pyrazol-1-yl]-ethanone 2.41(3H, s), 2.10(3H, s), 1.99-2.05(5H, m). 654-(7-Methoxy-6-methyl- δ6.47(1H, s), 4.35(2H, q), 343 (M⁺ + 1) 2947,1738, indan-4-ylmethyl)-3,5- 3.66(3H, s), 1605, 1484.dimethyl-pyrazole-1- 3.57(2H, s), 2.87(2H, t), carboxylic acid ethyl2.75(2H, t), 2.38(3H, s), 2.09(3H, ester s), 1.93-2.04(5H, m), 1.32(3H,t). 66 Propane-2-sulfonic acid δ11.50(1H, bs), 6.49(1H, s), 4.12(2H, 446(M⁺ − 1) 2943, 1710, {3-[4-(7-methoxy- t), 1462, 1406 6-methyl-indan-4-3.64(3H, s), ylmethyl)-3,5-dimethyl- 3.51-3.55(1H, m), 3.47(2H, s),pyrazol-1-yl]-propionyl}- 2.80-2.88(4H, m), 2.73(2H, t), amide 2.09(3H,s), 2.08(3H, s), 1.96-2.03(2H, m), 1.91(3H, s), 1.20(6H, d). 673-[5-Ethoxy-4-(7- δ6.57(1H, s), 4.02(2H, t), 373 (M⁺ + 1) 2926, 1731,methoxy-6-methyl- 3.92(2H, q), 3.65(3H, s), 3.49(2H, 1577, 1479indan-4-ylmethyl)-3- s), 2.87(2H, t), methyl-pyrazol-1-yl]-2.64-2.77(4H, m), 2.09(3H, s), propionic acid 1.98-2.04(2H, m), 1.91(3H,s), OR 1.21(3H, t). 3-[3-Ethoxy-4-(7- methoxy-6-methyl-indan-4-ylmethyl)-5- methyl-pyrazol-1-yl]- propionic acid 68[4-(7-Hydroxy-3,6- δ8.10(1H, s), 6.33(1H, s), 329 (M⁺ + 1) 3428, 2949dimethyl-indan-4- 4.76(2H, s), 3.52(2H, d), 3.27(1H, 1715, 1483ylmethyl)-3,5-dimethyl- merged with peak of pyrazol-1-yl]-acetic acidwater present in DMSO- d₆), 2.74-2.78(2H, m), 2.05-2.10(1H, m), 2.00(3H,s), 1.99(3H, s), 1.90(3H, s), 1.67-1.72(1H, m), 1.09(3H, d). 692-[4-(7-Hydroxy-6- δ12.33(2H, bs), 8.09(1H, s), 399 (M⁺ − 1) 3367, 2957,methyl-indan-4- 6.54(1H, s), 1734, 1483 ylmethyl)-3,5-dimethyl-4.12-4.17(1H, m), pyrazol-1-ylmethyl]- 3.92-3.97(1H, m)3.43(2H, s),pentanedioic acid 2.81-2.86(1H, m), 2.74(2H, t), 2.68(2H, t),2.15-2.17(2H, m), 2.06(3H, s), 2.01(3H, s), 1.89-1.98(5H, m),1.63-1.69(2H, m). 70 [4-(7-Methoxy-2,2,6- δ12.8(1H, bs), 6.52(1H, s),355 (M⁺ − 1) 2952, 1716, trimethyl-indan- 4.77(2H, s), 1574, 14784-ylmethyl)-3,5- 3.62(3H, s), 3.47(2H, s), dimethyl-pyrazol-1- 2.67(2H,s), 2.57(2H, s), 2.07(3H, yl]-acetic acid s), 2.03(3H, s), 1.91(3H, s),1.10(6H, s). 71 N-{2-[4-(7-Methoxy-6- δ7.97(1H, t), 6.51(1H, s), 356(M⁺ + 1) 3316, 1644, methyl-indan-4- 3.96(2H, t), 3.64(3H, s), 3.46(2H,1544, 1478 ylmethyl)-3,5-dimethyl- s), 3.31(2H, merged withpyrazol-1-yl]-ethyl}- peak of water present in acetamide DMSO- d₆),2.86(2H, t), 2.74(2H, t), 2.09(3H, s), 2.07(3H, s), 1.96-2.01(2H, m),1.93(3H, s), 1.77(3H, s). 72 N-{2-[4-(7-Methoxy-6- δ7.19(1H, t),6.50(1H, s), 392 (M⁺ + 1) 3111, 1573, methyl-indan-4- 4.00(2H, t),3.64(3H, s), 3.49(2H, 1475, 1384 ylmethyl)-3,5-dimethyl- s), 3.28(2H,merged with pyrazol-1-yl]-ethyl}- peak of water present inmethanesulfonamide DMSO- d₆), 2.86(2H, t), 2.73-2.79(5H, m), 2.11(3H,s), 2.08(3H, s), 1.94-2.03(5H, m). 73 4-[4-(7-Methoxy-6- ¹H-NMR (400MHz, CDCl₃) 508 (M⁺ + 1) 2949, 1485, methyl-indan-4- δ7.68(2H, d),7.34(2H, d), 1443, 1330 ylmethyl)-3,5-dimethyl- 6.47(1H, s),pyrazol-1-yl]-1-(toluene- 3.92-3.94(2H, m), 4-sulfonyl)-piperidine3.81-3.89(1H, m), 3.73(3H, s), 3.52(2H, s), 2.94(2H, t), 2.77(2H, t),2.42-2.48(5H, m), 2.28-2.38(2H, m), 2.15(3H, s), 2.05-2.11(5H, m),2.02(3H, s), 1.90-1.93(2H, m). 74 {3,5-Diethyl-4-[6-(4- δ8.29(1H, s),437 (M⁺ + 1) 2974, 1734, fluoro-benzyl)- 7.08-7.13(2H, m), 6.99(2H, t),1604, 1506 7-hydroxy-indan-4- 6.45(1H, s), 4.73(2H, s), 3.75(2H,ylmethyl]-pyrazol-1-yl}- s), 3.45(2H, s), 2.76(2H, t), acetic acid2.70(2H, t), 2.37(2H, q), 2.26(2H, q), 1.92-1.99(2H, m), 0.94(3H, t),0.82(3H, t). 75 3-{4-[7-Methoxy-6-(4- 433 (M⁺ − 1) 2945, 1737,methoxy-phenyl)-indan- 1608, 1569 4-ylmethyl]-3,5-dimethyl-pyrazol-1-yl}-propionic acid 76 2-[3,5-Diethyl-4-(7- δ8.12(1H, s),7.73(1H, d), 384 (M⁺ + 1) 3249, 2972, hydroxy-6-methyl-indan- 6.40(1H,s), 4.58(2H, s), 1756, 4-ylmethyl)-pyrazol-1-yl]- 3.81-3.83(1H, m),3.48(2H, s), 1658. N-isopropyl-acetamide 2.72-2.78(4H, m), 2.44(2H, q),2.31(2H, q), 1.93-2.02(5H, m), 1.07(3H, s), 1.05(3H, s), 1.00(3H, t),0.90(3H, t). 77 3-[4-(7- δ6.58(1H, s), 4.24(2H, q), 415 (M⁺ + 1) 1743,1618, Ethoxycarbonyloxy-6- 4.16(2H, t), 3.58(3H, s), 3.55(2H, 1564, 1473methyl-indan-4- s), ylmethyl)-3,5-dimethyl- 2.69-2.83(6H, m), 2.12(3H,s), pyrazol-1-yl]-propionic 1.98-2.09(5H, m), 1.94(3H, s), acid methylester 1.28(3H, t). 78 Sodium salt of [3,5- δ6.62(1H, s), 4.28(2H, s),343 (M⁺ + 1) 1613, 1562, Diethyl-4-(7-hydroxy-6- 3.38(2H, merged withpeak of 1469, 1400 methyl- water present in DMSO- indan-4-ylmethyl)-d₆), pyrazol-1-yl]-acetic 2.65-2.70(4H, m), 2.38(2H, q), acid 2.30(2H,q), 1.85-1.99(5H, m), 1.00(3H, t), 0.90(3H, t). 79 3-[4-(7-Methoxy-6-δ6.52(1H, s, for major 381 (M⁺ − 1) 2936, 1738, methyl-indan-4- isomer),6.38(1H, s, for 1486, 1393 ylmethyl)-3-methyl-5- minor isomer), 5.04(2H,s, rifluoromethyl- for minor pyrazol-1-yl]-propionic isomer), 5.03(2H,s, for acid And major isomer), 3-[4-(7-Methoxy-6- 3.69(2H, s, for bothmethyl-indan-4- isomer), 3.58(3H, s, for ylmethyl)-5-methyl-3- bothisomer), 2.88(2H, t, for rifluoromethyl- both isomer), 2.75(2H, t, forpyrazol-1-yl]-propionic both isomer), 2.24(3H, s, for acid both isomer),1.97-2.05(5H, m, for both isomer). 80 [4-(4-Hydroxy-3-methyl- δ13.01(1H,bs), 7.95(1H, bs), 329 (M⁺ + 1) 2924, 1719, 5,6,7,8-tetrahydro- 6.36(1H,s), 4.80(2H, s), 1575, 1471 naphthalen-1- 3.44(2H, merged with peak ofylmethyl)-3,5-dimethyl- water present in DMSO- pyrazol-1-yl]-acetic acidd₆), 2.54-2.58(4H, m), 2.02(3H, s), 1.98(3H, s), 1.90(3H, s),1.65-1.70(4H, m). 81 [4-(7-Chloro-indan-4- For major isomer 373 (M⁺ − 1)2960, 1746, yloxy)-3-thiophen- δ7.82(1H, s), 7.47(1H, dd), 1560, 14632-yl-pyrazol-1-yl]- 7.22(1H, dd), 7.14(1H, d), acetic acid 7.05(1H, dd),6.63(1H, d), And 4.90(2H, s), 3.04(2H, t), 2.95(2H, t),[4-(7-Chloro-indan-4- 2.10-2.17(2H, m). yloxy)-5-thiophen-2-yl-pyrazol-1-yl]- acetic acid 82 {4-[7-Methoxy-6-methyl- δ12.81(1H,bs), 8.22(2H, d), 464 (M⁺ − 1) 2944, 1732, 2-(4-nitro-phenoxy)- 7.18(2H,d), 6.62(1H, s), 1595, 1503 indan-4-ylmethyl]-3,5- 5.40-5.42(1H, m),4.74(2H, s), dimethyl-pyrazol-1-yl}- 3.66(3H, s), acetic acid3.45-3.52(4H, m), 2.96-3.07(2H, m), 2.11(3H, s), 2.02(3H, s), 1.91(3H,s). 83 [5-Amino-4-(7-methoxy- For major isomer 422 (M⁺ + 1) 3336, 2942,6-methyl-indan-4- δ7.34(2H, d), 6.95(2H, d), 1729, 1613ylmethyl)-3-(4-methoxy- 6.53(1H, s), phenyl)-pyrazol-1-yl]- 4.88(2H, s),3.87(3H, s), acetic acid 3.65-3.67(5H, m), 2.90(2H, t), And 2.76(2H, t),[3-Amino-4-(7-methoxy- 1.99-2.05(5H, m). 6-methyl-indan-4-ylmethyl)-5-(4-methoxy- phenyl)-pyrazol-1-yl]- acetic acid 842-[3,5-Diethyl-4-(7- δ15-98(1H, bs), 12.42(1H, s), 408 (M⁺ − 1) 3239,2937, hydroxy-6-methyl-indan- 8.14(1H, s), 6.41(1H, s), 5.03(2H, 1719,1617 4-ylmethyl)-pyrazol- s), 3.50(2H, s), 1-yl]-N-(1H-tetrazol-5-2.74-2.76(4H, m), 2.50(2H, merged yl)-acetamide with DMSO-d6 peak),2.31(2H, q), 1.97-2.02(5H, m), 1.00(3H, t), 0.93(3H, t). ¹H-NMR (400MHz, CD₃OD) δ6.49(1H, s), 5.04(2H, s), 3.60(2H, s), 2.76-2.84(4H, m),2.54(2H, q), 2.43(2H, q), 2.02-2.08(5H, m), 1.06(3H, t), 0.99(3H, t). 851-Carboxymethyl-5-(5- For major isomer 459 (M⁺ − 1) 3564, 2903,chloro-thiophen-2-yl)-4- δ7.04(1H, d), 6.77(1H, d), 1744, 1681(7-methoxy-6-methyl- 6.28(1H, s), 5.24(2H, s), indan-4-ylmethyl)-1H-4.10(2H, s), 3.65(3H, s), pyrazole-3-carboxylic 2.91(2H, t), 2.83(2H,t), acid 2.00-2.09(5H, m). And 2-Carboxymethyl-5-(5-chloro-thiophen-2-yl)-4- (7-methoxy-6-methyl- indan-4-ylmethyl)-2H-pyrazole-3-carboxylic acid $Average values are provided for NMRFollowing Compounds can Also be Prepared Using the Process MentionedAbove:

-   86. 3-[4-(1H-Indol-5-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionic    acid;-   87. [4-(1H-Indol-5-yloxy)-3,5-dimethyl-pyrazol-1-yl]-acetic acid;-   88.    2-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionic    acid;-   89.    1-{2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetyl}-pyrrolidine-2-carboxylic    acid;-   90.    [3,5-Diethyl-4-(7-hydroxy-6-pyrrolidin-1-ylmethyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic    acid;-   91.    3-[3,5-Diethyl-4-(7-hydroxy-6-pyrrolidin-1-ylmethyl-indan-4-ylmethyl)-pyrazol-1-yl]-propionic    acid;-   92.    3-[3,5-Diethyl-4-(7-methoxy-6-methoxymethyl-indan-4-ylmethyl)-pyrazol-1-yl]-propionic    acid;-   93.    {3,5-Diethyl-4-[7-hydroxy-6-(pyrrolidine-1-carbonyl)-indan-4-ylmethyl]-pyrazol-1-yl}-acetic    acid;-   94.    [3,5-Diethyl-4-(7-methoxy-6-methoxymethyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic    acid;-   95.    3-{3,5-Diethyl-4-[7-hydroxy-6-(pyrrolidine-1-carbonyl)-indan-4-ylmethyl]-pyrazol-1-yl}-propionic    acid; and-   96.    N-(4-Chloro-phenyl)-2-[3,5-diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetamide.    Biological Activity

With the contemplation that metabolically active thyroid like compoundswhich will have minimal or no effect on appetite as well as will belesser affinity towards Thyroid Receptors would be better effective forthe treatment of various metabolic disorders such as obesity,dyslipidemia, atheresclerosis, insulin resistance and metabolicsyndrome. Compounds of the present invention were tested for theireffect on O2 consumption (metabolic effect), LDL cholesterol, glucoselevels, insulin levels and food consumption (appetite stimulant) andalso to assess transcriptional activity of thyroid hormone receptor byin vitro TRE (Thyroid receptor element) reporter assay for TRα1 andTRβ1.

Effect of Compounds on Transcriptional Activity of Thyroid HormoneReceptor (THR): THR α1 and THR β1.

Assay Procedure:—

COST cells were transiently transfected with pGAL4 (betagalactosidase)/Thyroid al or pGAL4/Thyroid β1 and pLucPur. The cellswere cotransfected with pLacZNorm for normalization of transfectionefficiency. Transfected cells were then treated with differentconcentrations of compounds of present invention, vehicle for 24 hours.

Cells were the lysed and luciferase activity was monitored in allsamples. Results were expressed as fold activation as compared tovehicle control.

Results:—Thyroid (α1/β1) Transactivation in COS7 Cells.

TABLE 2 α1 β1 Conc. Fold Fold Compound (uM) Activation ActivationVehicle Zero 1 1 (10 mM NaOH) T3 20 35 29 0.02 17 13 T2 20 20 27 2 14 160.2 7 4 0.02 1 2 1 20 1 1 2 20 1 1 3 20 1 1 7 20 3 1 8 20 3 1 9 20 2.5 2

The compounds of the present invention exhibited significantly lesstranscriptional activation of THR (α1) or THR (β1) as compared to T3 andT2 under experimental conditions.

In Vivo Assay

Experiment-1

Effect of Compounds on Oxygen Consumption, Food Consumption and HeartWeight.

Methodology:

C57BL6 mice (14-18 weeks age), fed for 8-12 weeks with High Fat Diet(45% kcal fat) were used for the study. The mice were placed inindividual housing for one week. The mice were then kept in oxymax cagesfor 48 h for acclimatization. Basal recordings of oxygen consumption andcarbon dioxide production for each mouse were recorded with indirectopen circuit calorimeter (Oxymax, Columbus Instruments, USA (Ling fu etal., Endocrinology (2004); 145(6); 2591-3). On the basis of body weightand basal oxygen consumption, mice were randomized and divided into twogroups.

I) Vehicle treated group

II) Test compound treated group

The mice were treated with vehicle and test compounds intraperitoneallyfor 7-15 days. On the day 8, Oxygen consumption was measured forindividual mouse 30 min after the drug treatment and % change withrespect to vehicle is calculated.

During the experiment food consumption was monitored daily. At the endof the experiment the animals were scarified and the heart weights wererecorded.

Results:

TABLE 3 Effect of test compounds on oxygen consumption, foodconsumption, body weight and heart weight increase in food increase inconsumption Heart weight increase with with Compound Dose in O2reference to reference to Nos. (μM/kg) cons vehicle vehicle T2 0.05 * T20.5 ** + + T2 2 ** ++ ++ T2 5 ** +++ ++ 1 11 * No change No change 211 * No change No change 3 11 ** No change No change 6 11 * No change Nochange 7 11 ** No change No change 8 11 ** No change No change 9 11 **No change No change 19  11 ** No change No change 20  11 ** No change Nochange 14  11 * No change No change For change in oxygen consumption: *= Increase <5%, ** = Increase >5% For change in food consumption: + =Increase by 5-10%, ++ = Increase by 10-20%, +++ increase by >20% Forchange in heart weight: + = Increase by 10-15%, ++ = Increase by 15-20%,+++ increase by >20%

The test compounds of the present invention showed increase in the O2consumption without significantly influencing the food consumption.

Experiment-2:

Effect of Compounds on Body Weight, LDL Cholesterol, OGTT, FastingGlucose and Fasting Insulin Levels:

Methodology:

Male C57BL6 mice were fed high fat diet (Research Diet, New Brunswick,N.J.). Mice were housed 3 animals per cage in a temperature-controlledfacility (22±2° C.) with 12-h light/dark cycle. The mice were fed withHigh fat diet (45% kcal) for 8-12 weeks before drug treatment started.DIO (Diet Induced Obese) mice were selected from the stock andrandomized into three groups with 15 animals in each group on the basisof their body weight and age.

Group I Vehicle (10 ml/kg) Group II Dose 1 Group III Dose 2

Before monitoring the basal parameters all the mice were acclimatizedfor the treatment by administering vehicle (0.02 M DiSodium hydrogenphosphate, 10 ml/kg i.p., b.i.d) for about 2 weeks. Then the animalswere treated with either test compound A or B of formula (I) at twodifferent doses for 6-12 weeks. The treatment was administeredintraperitoneally b.i.d. The effect of 6-12 weeks treatment on change inbody weight, body fat, LDL cholesterol, OGTT, fasting glucose andfasting insulin, was monitored.

A index of insulin resistance i.e. HOMA-IR was calculated usingfollowing formula—HOMA_IR Score=Fasting serum insulin(μU/ml)×fasting serumglucose(mmol/l)/22.5Results:

Test Parameter compound Vehicle Dose 1 Dose 2 Glucose (mg/dl) A 217.6 ±5.4  185.9 ± 5.5** 214.3 ± 6.5   B 240.51 ± 8.7   224.85 ± 6.2   210.43± 11.5*  Insulin (ng/ml) A 0.83 ± 0.14  0.38 ± 0.05** 0.53 ± 0.05* B0.90 ± 0.13 0.78 ± 0.08 0.74 ± 0.13  HOMA_IR A 2.26 ± 0.36  0.90 ±0.13** 1.35 ± 0.14* B 2.7 ± 0.4  2.3 ± 0.26  2 ± 0.4 LDL-C (mg/dl) A24.96 ± 1.13  15.18 ± 1.6#  13.73 ± 0.9#  B 30.0 ± 1.03 27.9 ± 1.05 26.5± 0.9*  Body fat pads A 2.67 ± 0.26  1.65 ± 0.17** 2.02 ± 0.12* (g) B3.56 ± 0.44  2.33 ± 0.24*  1.9 ± 0.18** N = 12 to 15/group; *P < 0.05;**P < 0.01; #P < 0.001

CONCLUSION

The 6-12 weeks treatment with Test compound A and B was found to beeffective in significantly reducing the body weight, body fat, LDLcholesterol, fasting plasma glucose, insulin and improved the insulinresistance, with respect to vehicle. The FIG. 1 also indicates that testcompound was also showed improved glucose tolerance in experimentalanimals.

Overall, it can be concluded that the compounds of the present inventionhave utility in various metabolic disease conditions such asdyslipidemia, insulin resistance, type II diabetes, obesity andmetabolic syndrome.

REFERENCES

-   WHO fact sheet, 2006-   Melnikova I. & Wages D. Nature Reviews Drug Discovery (2006); 5:    369-370-   Eberhard Ritz, Am. J Cardiol (2007); 100 [Suppl]: 53-60-   Young-Woo Park et al. Arch intern Med (2003); 163: 427-436-   Richard Ceska, Diabetes and Vascular Disease Research (2007); 4    (suppl): S2-S4 Kelly G S. Altern Med Rev (2000); 5(4): 306-333-   Burger' 6^(th) edition, vol 3, pp. 564-565-   WO200703419-   Liu Ye et al., JMC (2003); 46: 1580-88-   Abrams J J et. al. J. Lipid Res. (1981); 22: 323-38-   Aviram M. et. al. CUn. Biochem. (1982); 15: 62-66-   Ness G C. et. al. Biochemical Pharmacology, (1998); 56: 121-129-   Grover G J. et. al. Endocrinology, (2004); 145: 1656-1661-   Grover G J. et. al. Proc. Natl. Acad. Sci. USA, (2003);    100:10067-10072-   Paul Webb. Expert Opin. Investig. Drugs, (2004); 13(5): 489-500-   de Bruin et. al. J. CUn. Endo. Metab., (1993); 76: 121-126-   A. Lombardi. Immun Endoc and Metab Agents in Med Chem (2006); 6:    255-65-   Horst C., Biochem J. (1989); 261: 945-950-   WO200509433-   Amedeo columbano. Endocrinology (2006); 147(7): 3211-8-   Wing May Kong et al. Endocrinology (2004); 145: 5252-5258-   Horst et al., J Endocrinology (1995); 145: 291-297-   Ling fu et al., Endocrinology (2004); 145(6): 2591-3

1. A compound of formula (I)

Wherein, R¹ and R³ are the same or different, and are independentlyselected from H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, halo, CN, CF₃,—O—(C₁-C₆)alkyl, —CO₂—(C₁-C₆)alkyl, COOH, —CONH—(C₁-C₆)alkyl,—CONH-aryl, —NH₂, —CONH—R⁶, —CONR⁵, —C₁-C₃alkyl-aryl, —(C₁-C₃)alkyl-R⁶,—NH—(C₁-C₆)alkyl, —NHaryl, —NH—SO₂—(C₁-C₆)alkyl, —CH₂—NH—(C₁-C₆)alkyl,—CH₂—O—(C₁-C₆)alkyl, —C₁-C₃alkyl-NR⁵, R⁶, R⁷, wherein said C₁-C₆alkyland C₃-C₇ cycloalkyl are optionally substituted with one or moresubstituents selected from (C₁-C₆)alkyl, halo, cyano, —OH, oxo, —COOH,—O—(C₁-C₆)alkyl, —O-benzyl, —COO—(C₁-C₆)alkyl, —CONH—(C₁-C₆)alkyl,—CONR⁵, —CONH-aryl, —CONH-heteroaryl or —CH₂NR⁵; R² is selected from(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)alkenyl, (C₃-C₆)alkynyl,—C(O)—(C₁-C₃)alkyl-COOH, —(C₁-C₃)alkyl-COOH,—C(O)—(C₁-C₃)alkyl-COO-alkyl, —C(O)—C(O)O—(C₁-C₆)alkyl,—C(O)—(C₁-C₃)alkyl-NH—(C₁-C₆)alkyl, —C(O)—O—(C₁-C₆)alkyl, —C(O)NR⁵,—C(O)NH—(C₁-C₆)alkyl, —C(O)—(C₁-C₃)alkylaryl, —C(O)—(C₁-C₃)alkyl-R⁶, R⁶,R⁷, wherein said (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)alkenyl and(C₃-C₆)alkynyl are optionally substituted with one or more substituentsselected from perhaloalkyl, oxo, —C(O)OH, —C(O)—O—(C₁-C₃)alkyl,—C(O)—O—(C₁-C₃)alkylaryl, —C(O)—O—(C₁-C₃)alkyl-R⁶, —CONH₂,—CONH(C₁-C₃)alkyl, —C(O)NH-aryl, —C(O)NH—R⁶, —CONR⁵, —CONHNH₂,—C(═NH)NH—(C₁-C₆)alkyl, —C(═NH)NH₂, C(═NH)NHOH, —C(O)—R⁸,—C(O)NHSO₂(C₁-C₆) alkyl, —C(O)NHSO₂-aryl, —C(O)NHOH, —C(O)NHSO₂—R⁶,—C(O)NHNH—(C₁-C₆)alkyl, —C(O)NHNH-aryl, —CONH—(C₁-C₂)alkyl-aryl,—C(O)NH—(C₁-C₂)alkyl-R⁶, —CH₂NR⁵, —NH₂, —NH—(C₁-C₆)alkyl,—NH—C(O)—O—(C₁-C₃)alkyl, —NH—C(O)—(C₁-C₃)alkyl, —NHC(O)-aryl,—NHC(O)—(C₁-C₃)alkylaryl, —NHC(O)—R⁶, —NH—C(O)NR⁵, —NH—C(O)NH-aryl,—NHC(O)NH—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl, —NH—SO₂-aryl, —NH—SO₂—R⁶,halo, cyano, —OH, —O—(C₁-C₆)alkyl, —O-aryl, —O-heteroaryl,—O—(C₁-C₂)alkyl-aryl, —SO₃H, —SO₂NH-aryl, —SO₂NH—R⁶,—SO₂NH—(C₁-C₆)alkyl, R⁶ or R⁷; R⁵ together with the nitrogen atom towhich it is attached form a saturated or unsaturated (C₃-C₆) memberedring, which may further contain 1-2 heteroatoms selected from O, N and Sand which is optionally substituted with one or more substituentsselected from oxo, —COOH, halo, —OH, —O—(C₁-C₆)alkyl, and —(C₁-C₆)alkyl;R⁶ is selected from phenyl and 5-8 membered heteroaryl containing 1-4heteroatoms selected from O, N and S, wherein said heteroaryl or phenylring is optionally substituted with one or more substituents selectedfrom halogen, —OH, —O—(C₁-C₆)alkyl, -perhaloalkyl, —(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl, —SO₂(C₁-C₆)alkyl, cyano, —COOH, —C(O)O—(C₁-C₆)alkyl,—C(O)O—CH₂-aryl, —C(O)O-aryl, —CONH(C₁-C₃)alkyl, nitro, —NH₂,—NH—(C₁-C₆)alkyl, —NHC(O)— (C₁-C₆)alkyl, —NHC(O)-aryl,—NHSO₂(C₁-C₆)alkyl, —CONH₂, —SO₂—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl and—COR⁸; R⁷ is a 3-6 membered heterocyclic ring containing 1-4 heteroatomselected from O, N and S, wherein said heterocyclic ring is optionallysubstituted with one or more substituents selected from oxo, halogen,—O—(C₁-C₆)alkyl, —OH, —CF₃, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, cyano,—COOH, —C(O)O—(C₁-C₆)alkyl, —C(O)O—CH₂-aryl, —C(O)O-aryl, —NH₂,—NH—(C₁-C₆)alkyl, —NHC(O)—(C₁-C₆)alkyl, —NHC(O)-aryl, —CONH₂,—SO₂aryl(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —NHSO₂(C₁-C₆)alkyl and —COR⁸;R⁸ is an amino acid which is linked through its nitrogen atom; Z═O orNH; R⁴ is selected from P, Q and T;

wherein * indicates the point of attachment to Z, R⁹ is selected from—OH, —O-alkyl, —OSO₃H, halogen, —C(O)O—(C₁-C₆)alkyl, —C(O)NHR⁸,—OC(O)—(C₁-C₆)alkyl, —O-perhaloalkyl, —OC(O)O—(C₁-C₆)alkyl, —CONR⁵,—NHCO—(C₁-C₆)alkyl, —NHC(O)—O—(C₁-C₆)alkyl, —NHC(O)—O-aryl,—NHSO₂—(C₁-C₆)alkyl, —NHSO₂-aryl, —NHCONR⁵ and;

R¹⁰ is selected from H, Halogen, (C₁-C₆)alkyl, alkoxy, aryloxy,—NHCO—(C₁-C₆)alkyl, —NHSO₂—(C₁-C₆)alkyl and —NH—SO₂-aryl; R¹¹ is—CO—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl or —SO₂—aryl; G′ is selected from H,halogen and (C₁-C₆)alkyl; G″ is selected from hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, aryl, halogen, perhaloalkyl, CN, CHO,—(C₁-C₃)alkylaryl, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl, —CH₂R⁹, —CH₂aryl,—CH₂NR⁵, —COOH, —C(O)O(C₁-C₆)alkyl, —CONH—(C₁-C₆)alkyl, —CONR⁵, —SO₂NR⁵,—SO₂NH—(C₁-C₆)alkyl and —SO₂NH-aryl; n is 1 or 2; including theirpharmaceutically acceptable salts thereof with a proviso that: when R⁴is Q then, R² is other than R⁶ and R⁷.
 2. The compound as claimed inclaim 1, wherein R⁴ is selected from P and T.
 3. A compound which isselected from the group consisting of:3-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionicacid,7-[3,5-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-1H-pyrazol-4-yloxy]-indan-4-ol,7-{3,5-Dimethyl-1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-pyrazol-4-yloxy}-indan-4-ol,{2-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-acetylamimo}-aceticacid,2-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-N-(1H-tetrazol-5-yl)-acetamide,3-[4-(7-Hydroxy-indan-4-yloxy)-3-thiophen-2-yl-pyrazol-1-yl]-propionicacid,3-[4-(7-Hydroxy-indan-4-yloxy)-5-thiophen-2-yl-pyrazol-1-yl]-propionicacid,7-[1-(1H-Tetrazol-5-ylmethyl)-3-thiophen-2-yl-1H-pyrazol-4-yloxy]-indan-4-ol,7-[1-(1H-Tetrazol-5-ylmethyl)-5-thiophen-2-yl-1H-pyrazol-4-yloxy]-indan-4-ol,5-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-ylmethyl]-1H-pyrazol-3-ol,3-[3,5-Dicyclopropyl-4-(7-hydroxy-indan-4-yloxy)-pyrazol-1-yl]-propionicacid,[3,5-Dicyclopropyl-4-(7-hydroxy-indan-4-yloxy)-pyrazol-1-yl]-aceticacid,[4-(7-Hydroxy-6-methyl-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-aceticacid,7-[3,5-Dimethyl-1-(1H-tetrazol-5-ylmethyl]-1H-pyrazol-4-yloxy]-5-methyl-indan-4-ol,[4-(7-Hydroxy-6-methyl-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-aceticacid,3-[4-(7-Hydroxy-6-methyl-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionicacid, [4-(7-Chloro-indan-4-yloxy)-3-thiophen-2-yl-pyrazol-1-yl]-aceticacid, [4-(7-Chloro-indan-4-yloxy)-5-thiophen-2-yl-pyrazol-1-yl]-aceticacid, 3-[4-(1H-Indol-5-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionic acid,[4-(1H-Indo)-5-yloxy)-3,5-dimethyl-pyrazol-1-yl]-acetic acid and2-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionicacid, including their pharmaceutically acceptable salts thereof.
 4. Apharmaceutical composition comprising a therapeutically effective amountof one or more compounds as claimed in claim 1, optionally inassociation with pharmaceutically acceptable diluents or carriers.
 5. Amethod of treating obesity in a mammalian organism, including humanbeing, comprising administering to the said mammalian organism in needthereof, a therapeutically effective amount of a compound as claimed inclaim
 1. 6. A method of ameliorating insulin resistance in a mammalianorganism, including human being, comprising administering to the saidmammalian organism in need thereof, a therapeutically effective amountof a compound as claimed in claim
 1. 7. A method of treatingdyslipidemia in a mammalian organism, including human being, comprisingadministering to the said mammalian organism in need thereof, atherapeutically effective amount of a compound as claimed in claim
 1. 8.A method of treating metabolic syndrome in a mammalian organism,including human being, comprising administering to the said mammalianorganism in need thereof, a therapeutically effective amount of acompound as claimed in claim
 1. 9. A process for the preparation of acompound as claimed in claim 1, which comprises: (i) reacting a compoundof formula (II)

with a compound of formulaR²—Y wherein Y is a leaving group, in the presence of suitable base insuitable solvent or; (ii) reacting a compound of formula (III) or (IX)

with hydrazine hydrate or suitably substituted hydrazine of formulaR²NHNH₂; (v) reacting a compound of formula (IV)

with a compound R⁴OH or R⁴NH₂ in presence of base; wherein R¹, R², R³and R⁴ are as defined in claim
 1. 10. A pharmaceutical compositioncomprising a therapeutically effective amount of one or more compoundsas claimed in claim 3, optionally in association with pharmaceuticallyacceptable diluents or carriers.
 11. A method of treating obesity in amammalian organism, including human being, comprising administering tothe said mammalian organism in need thereof, a therapeutically effectiveamount of a compound as claimed in claim
 3. 12. A method of amelioratinginsulin resistance in a mammalian organism, including human being,comprising administering to the said mammalian organism in need thereof,a therapeutically effective amount of a compound as claimed in claim 3.13. A method of treating dyslipidemia in a mammalian organism, includinghuman being, comprising administering to the said mammalian organism inneed thereof, a therapeutically effective amount of a compound asclaimed in claim
 3. 14. A method of treating metabolic syndrome in amammalian organism, including human being, comprising administering tothe said mammalian organism in need thereof, a therapeutically effectiveamount of a compound as claimed in claim
 3. 15. The compound as claimedin claim 3, wherein the compound is7-[3,5-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-1H-pyrazol-4-yloxy]-indan-4-ol,including its pharmaceutically acceptable salts.